JP6017420B2 - Catheter assembly - Google Patents

Description

Detailed Description of the Invention

[Cross-reference of related applications]
This application is filed in the names of Thermodix, Inc. and U.S. S. No. 61 / 360,354, filed on June 30, 2011 as a PCT international patent application in the name of Chappa, Ralph, A. Claim priority of June 30, 2010).

〔background〕
Drug release from implanted medical devices has been shown to be beneficial for device function and treatment of various medical conditions. For example, drug delivery from the surface of the device can prevent cellular responses caused by the presence of the implantable device. In addition, the drug released from the device can prevent a state in which the functional lifetime of the device accompanying the implantation is shortened. The drug released from the device can also be directed to treating the affected area of the body.

  Some implantable devices simply have a drug applied to the device surface. Such formulations are generally undesirable because the drug can be easily removed from the surface during insertion.

  An implantable medical device having a thin polymer coating containing a therapeutic compound protects and controls the release of the drug from the device surface. Such devices have been found to be particularly effective in the treatment of circulatory diseases. However, these polymer coatings may not be optimal for devices involving the temporary insertion of medical devices into target tissues in the body.

〔Overview〕
One aspect of the present disclosure relates to a catheter assembly. The catheter assembly includes an expandable and foldable structure having an outer surface. The expandable and foldable structure is configured to expand between a contracted state and an expanded state. The covering is disposed on the outer surface of the expandable and foldable structure. The coating contains a bioactive agent. The sleeve is disposed on one surface of the covering. The sleeve is configured to expand between the compressed state and the expanded state and return to the compressed state. The sleeve defines a plurality of openings in the compressed state. When the expandable and foldable structure is in the contracted state, the outer diameter of the covering is smaller than the outer diameter of the sleeve, and when the expandable and foldable structure is in the expanded state, the outer diameter of the covering is It is larger than the outer diameter of the sleeve.

  Another aspect of the present disclosure relates to a catheter assembly. The catheter assembly includes an expandable and foldable structure having an outer surface. The expandable and foldable structure is configured to expand between a contracted state and an expanded state. The first covering is disposed on the outer surface of the expandable and foldable structure. The first coating contains a bioactive agent. The second coating is disposed on the first coating. The second coating contains a mixture of fatty acids. The sleeve is disposed on one surface of the second covering. The sleeve is configured to expand between a compressed state and an expanded state. The sleeve includes a plurality of rails that extend longitudinally between a first axial end and a second axial end disposed on the opposite side. The plurality of rails define a plurality of openings. The second coating can be contacted through the opening in the compressed state. The size of each opening is increased in the expanded state.

  Another aspect of the present disclosure relates to a catheter assembly. The catheter assembly includes an expandable and foldable structure having an outer surface. The expandable and foldable structure is configured to expand between a contracted state and an expanded state. The first covering is disposed on the outer surface of the expandable and foldable structure. The first coating contains a bioactive agent. The second coating is disposed on the first coating. The second coating contains a mixture of fatty acids. The sleeve is disposed on one surface of the second covering. The sleeve is configured to expand between a compressed state and an expanded state. The sleeve includes a body having an inner surface and an outer surface. The inner surface defines a bore in which the expandable and foldable structure is disposed. The body defines a plurality of openings that extend through the inner and outer surfaces. The plurality of openings define an area of the outer surface in the compressed state that is from about 40% to about 95% of the total surface area in the compressed state.

  Another aspect of the present disclosure relates to a sleeve for a catheter assembly. The sleeve includes a body having a first axial end, a second axial end disposed on the opposite side, an outer surface and an inner surface disposed on the opposite side. The body defines a bore that extends through the first and second axial ends and a plurality of openings that pass through the outer surface and the inner surface. The main body is configured to expand from the compressed state to the expanded state according to the force acting on the inner surface, and return to the compressed state when the force is removed. The plurality of openings define an area of the outer surface in the compressed state that is from about 40% to about 95% of the total surface area in the compressed state.

  Another aspect of the present disclosure relates to a catheter assembly that includes an expandable and foldable structure having an outer surface. The expandable and foldable structure is configured to expand between a contracted state and an expanded state. The expandable and foldable structure includes an end of the distal end and a proximal end disposed on the opposite side. The sleeve is disposed around the outer surface of the expandable and foldable structure. The sleeve includes a body having a first axial end, a second axial end disposed on the opposite side, an outer surface and an inner surface disposed on the opposite side. The body defines a bore in which at least a portion of the expandable and foldable structure is disposed. The bore extends through the first and second axial ends. The body defines a plurality of openings that pass through the outer surface and the inner surface. The body is configured to expand from a compressed state to an expanded state when the expandable and foldable structure is in an expanded state and to return from the expanded state to a compressed state when the expandable structure is in a contracted state. Yes. The plurality of openings define an area of the outer surface in the compressed state that is from about 40% to about 95% of the total surface area in the compressed state.

  Various further aspects will be described below. These aspects may relate to individual features and combinations of features. Both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the broad concepts based on the embodiments disclosed herein.

[Brief description of the drawings]
FIG. 1 is a side view of a catheter assembly having exemplary features of an embodiment in accordance with the principles of the present disclosure, with the expandable and foldable structure in a contracted state and the sleeve in a compressed state.

  2 is a cross-sectional view of the catheter assembly taken along line 2-2 of FIG.

  3 is a cross-sectional view of the catheter assembly taken along line 3-3 of FIG.

  4 is a cross-sectional view of the catheter assembly of FIG. 1 showing an optional protective layer.

  FIG. 5 is a cross-sectional view of the catheter assembly taken along line 5-5 of FIG.

  FIG. 6 is a cross-sectional view of the catheter assembly of FIG. 1 showing an optional release layer.

  7 is a cross-sectional view of the catheter assembly of FIG. 1 showing an optional second protective layer.

  FIG. 8 is a side view of another embodiment of a sleeve in a catheter assembly.

  FIG. 9 is a side view of another embodiment of a sleeve in a catheter assembly.

  FIG. 10 is a side view of another embodiment of a sleeve in a catheter assembly.

  FIG. 11 is a side view of the catheter assembly showing an alternative connection arrangement between the expandable and foldable structure and the sleeve.

  FIG. 12 is a side view of the catheter assembly showing an alternative connection arrangement between the expandable and foldable structure and the sleeve.

  FIG. 13 is a side view of a catheter assembly showing a second expandable and collapsible structure.

  FIG. 14 is a side view of a catheter assembly having an expandable and foldable structure in an expanded state and a sleeve in an expanded state.

  15 is a cross-sectional view of the catheter assembly taken along line 15-15 of FIG.

  FIG. 16 is a cross-sectional view of a catheter assembly in which a guide tube is disposed.

  FIG. 17 is another cross-sectional view of the catheter assembly in which the guide tube is disposed.

  FIG. 18 is another cross-sectional view of the catheter assembly in which the guide tube is disposed.

[Detailed explanation]
Reference will now be made in detail to exemplary aspects of the present disclosure that are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like structures.

  In FIG. 1, a catheter assembly 10 is shown. The catheter assembly 10 is configured to provide a drug delivery system that protects the drug layer when the catheter assembly 10 is guided to a target site.

  In the described embodiment, the catheter assembly 10 is configured for use in medical processes such as angioplasty. In the angioplasty process, the catheter assembly 10 is inserted into a patient's blood vessel and guided to a target site within the patient's vasculature. In one example, the target site is an obstruction in a blood vessel where there is an obstruction that restricts flow through the blood vessel.

  Catheter assembly 10 includes an expandable and foldable structure 12 and a sleeve 14. The expandable and collapsible structure 12 of the catheter assembly 10 is expanded from the contracted state (shown in FIG. 1) to the expanded state (shown in FIG. 18) at the target site, and then in the expanded state. Crushed into a contracted state. In one example, the expansion of the expandable and foldable structure 12 compresses the arthroma at the target site within the blood vessel. When the expandable and foldable structure 12 is in an expanded state, the covering disposed on the expandable and foldable structure 12 is carried around the target site tissue or the target site. Referring now to the figures of this disclosure, the catheter assembly 10 and use of the catheter assembly 10 will be further described.

  With reference now to FIGS. 1 and 2, the expandable and foldable structure 12 includes a distal end 16 and a proximal end 18, and the distal end 16 and the proximal end 18 are A central longitudinal axis 20 extending therethrough is defined. The expandable and foldable structure 12 has an outer surface 22 that extends between the distal end 16 and the proximal end 18 and an inner surface 24 disposed on the opposite side. The expandable and foldable structure 12 further includes a guide path 26 that extends through the distal end 16 and the proximal end 18. The guide path 26 is configured to receive a guidewire 28 that allows the catheter assembly 10 to travel to a target site within a blood vessel of the patient's body.

  The expandable and foldable structure 12 defines a lumen 30 that is disposed between the inner surface 24 of the expandable and foldable structure 12 and the guide path 26. The lumen 30 is configured to receive a liquid (eg, saline) for expanding the expandable and foldable structure 12 to an expanded state. As the liquid is transferred to the lumen 30, the liquid applies an external force radially on the inner surface 24 of the expandable and foldable structure 12. This radial external force causes the expandable and foldable structure 12 to expand into an expanded state. When the liquid in the lumen 30 is drained, the expandable and foldable structure 12 collapses or contracts to a contracted state.

  2 and 3, the expandable and foldable structure 12 includes a covering 32 that is arranged to cover the outer surface 22 of the expandable and foldable structure 12. A coating suitable for use as the coating 32 in the catheter assembly 10 is US patent application Ser. No. 61 / 360,212 filed Jun. 30, 2010 having attorney docket number 13288.0083 USP1. ("Lipid Coating for Medical Devices Delivering Bioactive Agent"), which is incorporated herein by reference in its entirety.

  The covering 32 includes a plurality of covering layers. In the embodiment shown in FIG. 2, the coating 32 includes a drug coating 34. The drug coating 34 is configured to locally administer the bioactive agent to a target site within the patient's body.

Coatings Current medical devices can include any of a variety of coatings that include bioactive agents. A large number of suitable coating materials and polymers useful in such coatings are described herein. One embodiment suitable for releasing bioactive agent from an expandable and foldable structure can release an effective amount of bioactive agent within seconds or minutes at the delivery site. The bioactive agent can be in an amorphous form incorporated into the dressing or polymer matrix of the coating.

  The coating containing the bioactive agent may be present on one or more parts of the expandable and foldable structure, eg, one or more parts of the outer surface. The coating containing the bioactive agent can cover the entire surface of the balloon portion of the balloon catheter. As such, when the balloon is expanded in place, the bioactive agent can be moved to the outer periphery of the lumen in the artery.

  The coating containing the bioactive agent can cover less than the entire surface of the expandable and foldable structure, such as a discontinuous pattern. A “discontinuous” coating refers to a coating material that does not cover a structure (eg, the entire surface of a balloon), but is preferably formed on one or more portions of the surface. The discontinuous coating pattern facilitates delamination of the biodegradable coating material from the expandable and foldable surface when expanded. In some embodiments, there is little or no possibility that the discontinuous biodegradable coating will break before peeling from the surface. In other embodiments, the discontinuous biodegradable coating can have a friable pattern that facilitates release. From the standpoint of inflation pressure, a discontinuous biodegradable coating will require less force for delamination of the coating.

  A biodegradable coating having a discontinuous pattern can be formed directly on the expandable and foldable surface of the balloon. Alternatively, it can be formed in conjunction with other coating materials, such as, for example, a flexible hydrogel layer. Discontinuous patterns such as dots and stripes can be formed using spray coating processing equipment.

  The coating containing the bioactive agent can be a flexible hydrogel matrix. The flexible hydrogel matrix can consist of a hydrophilic polymer that is biostable. The polymer can be covalently bonded to the expandable and foldable structure, can be covalently bonded to other hydrophilic polymers in the matrix, or both. In some desirable embodiments, the biostable hydrophilic polymer is one that is attached to the substrate surface via reacted photogroups.

  The coating containing the bioactive agent can include a water soluble polymer, such as a water soluble polymer such as poly (vinyl pyrrolidone). In some cases, the coating includes a polymer that is covalently bonded to the surface of the expandable and foldable structure via a photoreactive group. The coating can also be formed from a composition in which the water-soluble polymer is in the macromer form.

  In one embodiment, at least a portion of the coating containing the bioactive agent can be peeled away by expansion within the subject and expansion of the foldable structure. A detached biodegradable polymer matrix having a bioactive agent can be adhered to a target tissue, for example. Degradation of the peeled polymer matrix and release of the bioactive agent can occur at the target site. The biodegradable polymer matrix can be used integrated with a flexible hydrogel matrix. The flexible hydrogel matrix can be a coating for release. The biodegradable polymer matrix can include a bioactive agent.

  In certain embodiments, the bioactive agent can be incorporated and / or attached to a biodegradable coating that is present on the expandable and collapsible structure and can be crushed. In the unexpanded state, the bioactive material is substantially or entirely confined within the coating, adhered to the coated layer, or both. In substrate expansion, the coating breaks and peels from the expandable and foldable surface. Thus, the coating can have rigid and brittle characteristics. At the target site, the portion of the coating is delivered to the tissue along with the incorporated bioactive agent. In some cases, the portion of the coating carried can adhere to the tissue and provide a barrier or coating to improve the fixation of the coating. In synchronization with the degradation of the biodegradable coating material, the bioactive agent can be released to provide a therapeutic effect.

  Current medical devices can include any of a variety of coatings that assist in delivering the bioactive agent. Such coatings include release coatings and adhesion coatings. A large number of suitable coating materials and polymers useful in such coatings are described herein.

  In one embodiment, current medical devices include an adhesive dressing. The adhesive dressing can be on an expandable and contractible structure and can facilitate adhesion of the drug coating to the subject's tissue at the delivery site. For example, the adhesive dressing can be on the drug coating. For example, an adhesive component can be present in the drug coating. The adhesive dressing can include half of the cation or adhesive protein. The adhesion protein can be or can include collagen, heparin, laminin, and mixtures thereof. In one embodiment, the adhesive dressing can provide an adhesive material for bonding to damage, such as vascular damage. Damage components that can cause adhesion include cells, collagen, cholesterol, lipoproteins, or calcification.

  The device can include a degradable coating layer between the coating containing the bioactive agent and the surface of the expandable and foldable structure. For example, the decomposable layer can be present as a base coat on the surface of the expandable and foldable structure.

Coating polymer The coating may be formed from a polymeric material (one or more polymers) that allows immobilization of the bioactive agent in an unexpanded state. The polymeric material can include one or more homopolymers, copolymer matrices, combinations or mixtures thereof effective to form the matrix. In one aspect, the polymeric material is used to form a flexible hydrogel matrix as a coating.

  In some methods of preparation, a coating composition is formed that includes one or more matrix-forming polymers and a bioactive agent. In general, the coating material is selected and used from among compositions suitable for forming a matrix with a bioactive agent. In one implementation, the hydrophilic polymer is used to prepare a liquid composition that also includes a bioactive agent. Bioactive agents are water-insoluble, that is, those that do not readily dissolve in water.

  In other cases, the bioactive agent is not included in the coating composition having one or more matrix-forming polymers. In such a coating process, the bioactive agent is used in a subsequent coating process that is integrated into the coated polymer matrix.

  Generally, the coating composition contains an amount and type of polymeric material that provides suitable physical properties (such as elasticity and bioactive agent retention). In certain embodiments, the amount of polymeric material used to form the matrix in the composition is about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg in concentration. / ML to about 20 mg / mL. In one example of a method of implementation, the polymeric material is about 15 mg / mL and is present in the coating composition.

  The polymeric material can also include pendent photo-reactive groups or polymerizable groups that can be activated to form a crosslinked matrix of the polymer. Also, the amount of polymer in the composition can be selected based on the level of derivatization of these groups.

  A class of hydrophilic polymers that are effective as polymeric materials for matrix formation are synthetic hydrophilic polymers. Synthetic hydrophilic polymers that are biostable (ie do not exhibit appreciable degradability in vivo) are acrylic monomers, vinyl monomers, ether monomers, or one of those monomers. It can also be prepared from any suitable monomer containing a combination of the above types. Acrylic monomers include, for example, methacrylic resin, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, methacrylic acid, acrylic acid, glycerol acrylate, glycerol methacrylate, acrylamide, methacrylamide, dimethylacrylamide (DMA), And / or derivatives, and / or mixtures of any of these. Vinyl monomers include, for example, vinyl acetate, vinyl pyrrolidone, vinyl alcohol, and any derivatives thereof. Ether monomers also include, for example, ethylene oxide, propylene oxide, butylene oxide, and derivatives of any of these.

  Examples of polymers that can be formed from these monomers are poly (acrylamide), poly (methacrylamide), poly (vinyl pyrrolidone), poly (acrylic acid), poly (ethylene glycol), poly (vinyl alcohol), poly (HEMA) is included. Examples of hydrophilic copolymers include, for example, methyl vinyl ether / maleic anhydride copolymer and vinyl pyrrolidone / (methyl) acrylamide copolymer. Mixtures and / or copolymers of homopolymers may be used.

  Examples of some acrylamide-based polymers, such as poly (N, N-dimethylacrylamide-co-aminopropylmethacrylamide) and poly (acrylamide-co-N, N-dimethylaminopropylmethacrylamide) are It is described in Example 2 of US Patent Publication No. 2006/0030669 (filed September 17, 2004, Teton et al.), Incorporated herein by reference and filed on September 17, 2004. .

  In certain embodiments, the hydrophilic polymer is a vinyl pyrrolidone polymer or a vinyl pyrrolidone / (meth) acrylamide copolymer such as poly (vinyl pyrrolidone-co-methacrylamide). If a PVP copolymer is used, it can be a monomer selected from a polymer of vinyl pyrrolidone and an acrylamide monomer group. Examples of acrylamide monomers are (meth) acrylamide and (meth) acrylamide derivatives, such as alkyl (meth) acrylamides such as dimethylacrylamide and aminoalkyl (meth) such as aminopropylmethacrylamide and dimethylaminopropylmethacrylamide. Contains acrylamide. For example, poly (vinylpyrrolidone-co-N, N-dimethylaminopropyl methacrylamide) is described in Example 2 of US Patent Publication No. 2006/0030669 (Tayton et al.).

  In one embodiment, polymers and copolymers as described are derivatized with one or more photoactivatable groups (s). Examples of photoactive groups that can be provided by biostable hydrophilic polymers include allyl ketones such as acetophenone, benzophenone, anthraquinone, anthrone, quinone and anthrone-like heterocycles It is out. This applies to expandable and foldable structures, and then activates photogroups to generate sufficient actinic radiation to generate covalent bonds to targets such as expandable and foldable structure materials. Hydrophilic polymers with pendent activatable photo groups that can be treated with are obtained. The use of a photo-hydrophilic polymer provides a durable coating of a flexible hydrogel matrix on the hydrophilic polymer material that is covalently bonded to the expandable and foldable structural material.

  Hydrophilic polymers with pendant photoactive groups can be used to prepare flexible hydrogel coatings. Methods for preparing hydrophilic polymers with photoactive groups are well known in the prior art. For example, a method for preparing photo-PVP is described in US Pat. No. 5,414,075, the disclosure of which is incorporated herein by reference. A method for preparing photo-polyacrylamide is described in US Pat. No. 6,007,833, the disclosure of which is hereby incorporated by reference.

  In other embodiments, polymers and copolymers as described are derivatized with one or more polymerizable groups. Polymers having pendant polymerizable groups are commonly referred to as macromers. The polymerizable group may be present along the end of the polymer strand (terminal) or along the length of the polymer. In one embodiment, the polymerizable groups are randomly placed along the length of the polymer. The polymerizable group is activated to form a cross-linked matrix to which the bioactive agent is immobilized.

  Optionally, the coating can include a cross-linking agent. The cross-linking agent can promote integration with the polymer in the coating or binding of the polymer to the coated surface. The selection of a particular crosslinking agent can depend on the components of the coating composition.

  Suitable crosslinking agents contain two or more activatable groups that can react with the polymer in the composition. Suitable activating groups are described herein and include photoreactive groups such as alkyl ketones such as acetophenone, benzophenone, anthraquinone, anthrone, quinone and anthrone-like heterocycles.

  Photoactivatable cross-linking agents can be ionic and can have good solubility in aqueous compositions. Accordingly, in some embodiments, at least one ionic photoactivatable crosslinking agent is used to form the coating. The ionic crosslinking agent can include an acidic group or salt thereof, such as selected from sulfonic acids, carboxylic acids, phosphonic acids, salts thereof, and the like. Examples of counter ions include alkalis, alkaline earth metals, ammonium, protonated amines, and the like.

  Examples of ionic photoactivatable cross-linking agents are 4,5-bis (4-benzoylphenylmethyleneoxy) benzene-1,3-disulfonic acid or salt; 2,5-bis (4-benzoylphenylmethyleneoxy) ) Benzene-1,4-disulfonic acid or salt; 2,5-bis (4-benzoylmethyleneoxy) benzene-1-sulfonic acid or salt; N, N-bis [2- (4-benzoylbenzyloxy) ethyl] -2-aminoethanesulfonic acid or salt is included. See US Pat. No. 6,278,018. This disclosure is incorporated herein by reference.

  Natural polymers can also be used to form the matrix. Natural polymers include, for example, polysaccharides such as polydextran, carboxymethylcellulose, and hydroxymethylcellulose; glycosaminoglycans such as hyaluronic acid; polypeptides such as soluble proteins such as collagen, albumin and avidin; and these Contains a combination of natural polymers. Combinations of natural and synthetic polymers can also be used.

  In one embodiment, the bioactive agent includes a first polymer having a lower Tg than the second polymer. A harder second polymer can reduce the release rate of the bioactive agent in the matrix. For example, a suitable first polymer, such as PLGA, has a Tg of approximately 45 ° C. A suitable second polymer, such as PLLA, has a Tg of approximately 55 ° C. In some embodiments, the difference in Tg between the first and second polymers is approximately 5 ° C. or greater. In a more detailed embodiment, the difference in Tg between the first and second polymers is approximately 10 ° C. or higher. In certain embodiments, the first and second polymers have a Tg of about 35 ° C. or greater. In more detailed embodiments, the first and second polymers have a Tg in the range of about 35 ° C to about 65 ° C.

  The selection of the first and second polymers may also be based on other properties of the polymer such as molecular weight, solubility, and rheology.

  In certain embodiments, the polymer matrix comprises an amphiphilic copolymer, a low molecular weight hydrophobic polymer, an organogel, a variable hydrogel, a plurality thereof, or a mixture thereof. In one embodiment, the coating that includes the bioactive agent includes an amphiphilic copolymer or is made of an amphiphilic copolymer. Suitable amphiphilic copolymers include lactide / glycolide / caprolactone / polyethylene glycol copolymers. Such copolymers contain polyethylene glycol blocks. Although not limited to this disclosure, amphiphilic copolymers are believed to include a hydrophobic region that enhances the solubility of the hydrophobic drug and a hydrophilic region that absorbs water so that the coating expands when immersed in blood. It has been.

  In one embodiment, the coating that includes the bioactive agent includes or is made of a low average molecular weight hydrophobic polymer. Suitable low molecular weight hydrophobic polymers include polylactide / glycolide / caprolactone copolymers.

  In one embodiment, the drug coating includes one or more solvents and a bioactive agent. In one embodiment, the drug coating includes an organogel. In one embodiment, the drug coating includes a variable hydrogel.

  In one embodiment, the drug coating includes a lipid. Without being limited to the present disclosure, lipids can enhance the adhesion and penetration of drugs into tissues. The drug can be emulsified into a lipid carrier.

  In one embodiment, the drug is dissolved or dispersed in a variable polymer layer, such as, for example, a hydrophobic polymer, organogel, or variable hydrogel. In one embodiment, such a coating can flow out or leak out of the balloon surface and can fit or adhere to tissue on the expansion of the balloon.

Biodegradable polymer A biodegradable polymer is one or more (eg, 1, 2, 3, or 4) specific biodegradable polymers for use in forming an implant in vivo. Can be included. Suitable polymers are biodegradable and will dissolve well in a biocompatible solvent system. In particular, the biodegradable polymer may have a solubility of at least about 50 g / L at 25 ° C. and 1 atmosphere in a biocompatible solvent system. In one embodiment, the biodegradable polymer will not include a polymer that is sufficiently insoluble in a biocompatible solvent system. In one embodiment, the biodegradable polymer will not include a biodegradable polymer that is sufficiently insoluble in water or body fluids.

  Suitable specific types of polymers include, for example, polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamine, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal, polyketal, polycarbonate, polyorthocarbonate, polyphosphazene. , Succinate, poly (malic acid), poly (amino acid), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, and copolymers, block copolymers, multiblock copolymers, polyethylene Multiblock copolymers, polyols, terpolymers and mixtures thereof with glycol (PEG) are included.

  In one embodiment, the biodegradable polymer is a thermoplastic polymer.

  In one embodiment, the biodegradable polymer has a viscosity of at least about 100 cP at 37 ° C. In other embodiments, the biodegradable polymer has a viscosity of about 1000 cP to about 30000 cP at 37 ° C., a viscosity of about 5000 cP to about 25000 cP at 37 ° C., or a viscosity of about 10000 cP to about 20000 cP at 37 ° C. doing.

  In one embodiment, the biodegradable polymer is hydrophobic.

  In one embodiment, the biodegradable polymer includes a block copolymer. In one embodiment, the biodegradable polymer is polyethylene glycol (PEG) that includes a triblock copolymer.

  In one embodiment, the polymer contains functional side groups.

  The biodegradable polymer can be present in an appropriate and effective amount if the biodegradable polymer is sufficiently soluble in the solvent system, and in combination with the solvent system in vivo. Will form an implant. In one embodiment, the biodegradable polymer is present from about 10 wt% to about 40 wt% of the formulation. In one embodiment, the biodegradable polymer is present from about 40 wt% to about 90 wt% of the formulation.

  In one embodiment, the biodegradable polymer can include a poly (ether ester) multiblock copolymer sold, for example, under the trade name SynBiosys ™. In one embodiment, the biodegradable polymer can include a polyglycerol fatty acid ester. In one embodiment, the biodegradable polymer can include a PEG-PBT polymer. In one embodiment, the biodegradable polymer can comprise a poly (ester-amide) polymer (PEA).

Poly (ether ester) multiblock copolymers One suitable class of biodegradable polymers includes poly (ether ester) multiblock copolymers. These multiblock copolymers constitute various prepolymers that make blocks of various combinations of DL-lactide, glycolide, ε-caprolactone and polyethylene glycol. By varying the molecular composition, molecular weight (Mw 1200-6000) and prepolymer block ratio, different functional groups can be transferred to the final polymer that allows creation of polymers with different physiochemical properties . Both hydrophilic / swellable and hydrophobic polymers, as well as slowly and rapidly degrading polymers can be designed.

  The poly (ether ester) multi-block copolymer may include a polymer as shown below (Chemical Formula III).

  Here, m and p are independent glycolides, n is a polyethylene glycol having a Mw of 300-1000, o is ε-caprolactone, and q is DL-lactide.

  Under physiological conditions, such poly (ether ester) multiblock copolymers can be hydrolyzed completely into non-toxic degradation products that are metabolized and / or excreted through the urinary pathway. obtain. As a result, there can be no accumulation of biocompatible material, thereby reducing the possibility of long-term foreign body reaction.

  For example, further features and descriptions of poly (ether ester) multiblock copolymers are provided in WO 2005/068533 and the references cited therein. A summary is provided below.

  Multiblock copolymers are connected by multifunction, especially aliphatic chain extenders, and are essentially essentially amorphous, especially under physiological conditions (wet environment, body temperature that is approximately 37 ° C. for humans). In particular, it may contain two hydrolyzable segments that are different in quality and have different configurations.

The resulting multi-block copolymer has a structure based on any one of the following chemical formulas (1) to (3).
[-R ₁ -Ql-R ₄ -Q2-] _x- [R ₂ -Q3-R ₄ -Q4-] _y- [R ₃ -Q5-R ₄ -Q6-] _z- (1)
[-R ₁ -R ₂ -R ₁ -Q1-R ₄ -Q2-] _X- [R ₃ -Q2-R ₄ -Q1] _Z- (2)
[-R ₂ -R ₁ -R ₂ -Q1-R ₄ -Q2-] _X- [R ₃ -Q2-R ₄ -Q1] z- (3)
Where R ₁ and R ₂ can be amorphous polyesters, amorphous polyether esters or amorphous polycarbonates; or are amorphous prepolymers obtained from mixed ester, ether and / or carbonate groups obtain. R ₁ and R ₂ can contain polyether groups, which can result from the use of these compounds as polymerization initiators. The polyether is amorphous or crystalline at room temperature. However, polyethers introduced in this way will become amorphous under physiological conditions. R ₁ and R ₂ are obtained from amorphous prepolymers or blocks A and B, respectively, and R ₁ and R ₂ are not identical. R ₁ and R ₂ can simultaneously contain a polyether group. In a specific embodiment, only one of them will contain a polyether group;
z is 0 or a positive integer;
R ₃ is a polyether such as poly (ethylene glycol) and may be present when (z ≠ 0), ie (z = 0). R ₃ will become amorphous under physiological conditions;
R ₄ is an aliphatic C ₂ -C ₈ alkylene group. This alkylene group is optionally substituted by C ₁ -C ₁₀ alkylene, the aliphatic group is linear or cyclic, R ₄ can be in particular a butylene, a — (CH ₂ ) ₄ — group, and a C ₁ — C ₁₀ alkylene side group may include protected S, N, P or O moiety;
x and y are both positive integers, specifically, both can be at least 1. The sum of x and y (x + y) may specifically be up to 1000, more specifically up to 500, or up to 100. Q1-Q6 is a binding unit obtained by reaction of a prepolymer having a multifunctional chain extender. Q1-Q6 is independently an amine, urethane, amide, carbonate, ester or anhydride. The event that all the linking groups Q are different is unusual and undesirable.

Typically, one type of chain extender can be used with three prepolymers with similar end groups resulting from the copolymer of formula (1) having six similar linking groups. If the prepolymers R ₁ and R ₂ terminate differently, there will be two types of groups Q: for example, Q1 and Q2 are the same between two bonded prepolymer segments R ₁ but R ₁ When R ₂ and R ₂ are combined, Q 1 and Q 2 are different. Obviously, when Q1 and Q2 are the same, they are the same type of group but are mirror images of each other.

In the copolymers of formulas (2) and (3), group Q1 and group Q2 are the same when there are two prepolymers, both terminated with the same end group (usually hydroxyl), When the prepolymer is terminated differently (eg, PEG, a diol-terminated and diacid-terminated “triblock” prepolymer). In the case of triblock prepolymers (R ₁ R ₂ R ₁ and R ₂ R ₁ R ₂ ), the outer segment should be essentially free of PEG. Otherwise, the ligation reaction by ring opening is not performed successfully. Only the inner block can be caused by PEG molecules.

  Chemical formulas (1), (2) and (3) show the results of the reaction of a bifunctional chain extender and a bifunctional prepolymer.

Referring to chemical formula (1), the polyester is also a multiblock having a structure (ab) n having segments that interchange a and b, or a structure (ab) r having a random distribution of segments a and b, or It can also be expressed as a segmented copolymer. Here, “a” corresponds to the segment R ₁ derived from the prepolymer (A), and “b” corresponds to the segment R ₂ derived from the prepolymer (B) (z = 0). Regarding (ab) r, the a / b ratio (corresponding to x / y in the chemical formula (1)) can be a unit element or far from the unit element. The prepolymer can be mixed in any desired amount and can be linked by a multifunctional chain extender, ie, a compound having at least two functional groups that can be used to chemically bond the prepolymer. In particular, this is a bifunctional chain extender. And if z ≠ 0, a presentation of the random distribution of all segments can be given by (abc) r. There, three different prepolymers (one is eg polyethylene glycol) are randomly distributed according to all possible ratios. The alternative distribution is given by (abc) n. In this specific example, two equal terminated prepolymers (a and c or b and c) are replaced by equivalent amounts (a + c = b or b + c = a) of differently terminated prepolymers b, respectively. Or it is replaced with a. These are, according to chemical formula (2) or (3), the aba and bab “triblock” prepolymers having the structures (aba) n and (bab) n chain extended by a bifunctional molecule. Yes.

  The method for obtaining a copolymer having a random distribution of a and b (and optionally c) is that a segment is in a copolymer such as (ab) n where the ratio of prepolymers a and b is 1. It is even more advantageous than when changing at. The composition of the copolymer can then only be determined by adjusting the length of the prepolymer. In general, the lengths of the segments a and b of the (ab) n surrogate copolymer are smaller than the blocks in the block copolymer having structure ABA or structure AB.

  The prepolymer in which the a and b (and optionally c) segments are formed in (ab) r, (abc) r, (ab) n and (abc) n are joined by a bifunctional chain extender. This chain extender is in particular a diisocyanate chain extender, but can also be a diacid or diol compound. If all the prepolymers contain hydroxyl end groups, the linking unit will be a urethane group. When the prepolymer (one of them) is carboxylic acid terminated, the binding unit is an amide group. Multiblock copolymers having structure (ab) r and structure (abc) r can be obtained by reaction of dicarboxylic acid-terminated prepolymers with diol chain extenders, or vice versa (diol-terminated prepolymers with diacid chain extenders). Polymer), which can be prepared by the use of a binder such as DCC (dicyclohexylcarbodiimide) forming an ester linkage. In (aba) n and (bab) n, the aba and bab prepolymers are also particularly linked by an aliphatic bifunctional chain extender, more specifically a diisocyanate chain extender.

  The term “random segment” copolymer refers to a copolymer having a random distribution (ie, not alternating) of segments a and b or (ab) r or segments a, b and c or (abc) r. .

PEG-PBT Polymers One suitable class of biodegradable polymers include poly (ethylene glycol) (PEG) and poly (butylene terephthalate) (PBT), which can be described by the general chemical formula IV below. Base poly (ether ester) multi-block copolymers are included.
[-(OCH ₂ CH ₂ ) _n -OC (O) -C ₆ H ₄ -C (O)-] _x [-O- (CH ₂ ) ₄ -OC (O) -C ₆ H ₄ -C (O )-] _y (IV)
Here, -C ₆ H ₄ -represents a divalent aromatic ring residue from each esterified molecule of terephthalic acid, and n represents a unit of ethylene oxide in each hydrophilic PEG block The number represents the number, x represents the number of hydrophilic blocks in the copolymer, and y represents the number of hydrophobic blocks in the copolymer.

  In a specific embodiment, n can be selected such that the molecular weight of the PEG block is between about 300 and about 4000. In a specific embodiment, x and y can each be independently selected such that the multi-block copolymer contains from about 55% to about 80% PEG by weight.

  Block copolymers have abundant physical properties (eg, hydrophilicity, adhesion, strength, malleability, degradability, durability) by changing the values of n, x and y in the copolymer structure. Flexible) and release characteristics of bioactive agents (eg, via controlled polymer degradation and swelling).

Polyesteramide One suitable class of biodegradable polymers includes polyesteramide polymers having subunits of formula (V).
-[-O- (CH ₂ ) _x -OC (O) -CHR-NH-C (O)-(CH ₂ ) _y -C (O) -NH-CHR-C (OH)-]-(V)
Here, x is C ₂ -C ₁₂ , y is C ₂ -C ₁₂ , and R is —CH (CH ₃ ) ₂ , —CH ₂ CH (CH ₃ ) ₂ , —CH (CH ₃ ) CH ₂ CH ₃ , —CH ₂ (CH ₂ ) ₂ CH ₃ , —CH ₂ C ₆ H ₅ , —CH ₂ (CH ₂ ) ₂ SCH ₃ or an amino acid moiety.

In a specific embodiment, C ₂ -C ₁₂ can be (C ₂ -C ₁₂ ) alkyl. In other embodiments, C ₂ -C ₁₂ is (C ₂ -C ₁₂ ) alkyl, which can optionally be substituted.

  Such polymers are described, for example, in US Pat. No. 6,703,040. A polymer of this nature can be described by the name x-aa-y. Where “x” represents an alkyl diol having x carbon atoms, “aa” represents an amino acid such as leucine or phenylalanine, y represents an alkyl dicarboxylic acid having y carbon atoms, and the polymer is a diol , Polymerization of dicarboxylic acids and amino acids. An example of this type of polymer is 4-leucine-4.

Poly (ester-amide) polymer (PEA)
One suitable class of biodegradable polymers includes poly (ester-amide) polymers. Such polymers can be prepared by polymerization of diols, dicarboxylic acids and α-amino acids via (DACA) _n- shaped ester and amide linkages. An example of (DACA) _n polymer is shown in Formula VI below. Suitable amino acids also include any natural or synthetic α-amino acid, especially neutral amino acids.

The diol can be HO— (CH ₂ ) _k —OH (ie, unbranched), branched diol (eg, polyethylene glycol), cyclic diol (eg, dianhydroxytol and cyclohexanediol) or ethylene glycol (eg, diethylene glycol, triethylene It may be any aliphatic diol containing an alkylene diol, such as an oligomer diol based on glycol, tetraethylene glycol, or poly (ethylene glycol)). Aromatic diols (eg, bisphenols) are more toxic and polymers based on them are less useful for these purposes because they have rigid chains that are less biodegradable.

  The dicarboxylic acid can be any aliphatic dicarboxylic acid, such as α-ω-dicarboxylic acid (ie, unbranched), branched dicarboxylic acid, cyclic dicarboxylic acid (eg, cyclohexanedicarboxylic acid). Aromatic diacids (such as phthalic acid) are more toxic, polymers based on them have a rigid chain structure, show poorer film-forming properties, and are much less prone to biodegradation So it is not very useful for these purposes.

  A specific PEA polymer has the chemical formula VI:

Here, k is 2-12 (eg, 2, 3, 4 or 6), m is 2-12 (eg, 4 or 8), and R is —CH (CH ₃ ) ₂ , _{-CH 2 CH (CH 3) 2} , -CH (CH 3) CH 2 CH 3, -CH 2 (CH 2) 2 CH 3, -CH 2 (C 6 H 5), or _-CH 2 _(CH 2) SCH ₃ .

  In a specific embodiment, A is L-phenylalanine (Phe-PEA) and A is L-leucine (Leu-PEA). In a specific embodiment, the ratio of Phe-PEA to Leu-PEA is 10: 1 to 1: 1. In other specific embodiments, the ratio of Phe-PEA to Leu-PEA is from 5: 1 to 2.5: 1.

  Additional features and descriptions of poly (ester-amide) polymers (PEA) are provided, for example, in US Reissue Patent No. 40,359, which is a reissue of US Patent No. 6,703,040.

Hydrophobic derivatives belonging to natural biodegradable polysaccharides One suitable class of biodegradable polymers includes hydrophobic derivatives of natural biodegradable polysaccharides such as those sold under the trade name Eureka ™ SOLO polymer. Is included. Hydrophobic derivatives of natural biodegradable polysaccharides refer to natural biodegradable polysaccharides having one or more hydrophobic pendant groups belonging to the polysaccharide. In many cases, the hydrophobic derivative contains a plurality of groups comprising hydrocarbon segments belonging to the polysaccharide. When multiple groups containing hydrocarbon segments are attached, they are collectively referred to as the “hydrophobic portion” of the hydrophobic derivative. Hydrophobic derivatives therefore contain a hydrophobic part and a polysaccharide part.

  The polysaccharide moiety includes natural biodegradable polysaccharides that refer to non-synthetic polysaccharides that are enzymatically degradable. Natural biodegradable polysaccharides include polysaccharides and / or polysaccharide derivatives obtained from natural resources such as plants or animals. A natural biodegradable polysaccharide is any polysaccharide that has been processed or modified from a natural biodegradable polysaccharide (eg, maltodextrin is a natural biodegradable polysaccharide processed from starch). It also contains sugars. Examples of natural biodegradable polysaccharides are maltodextrin, amylose, cyclodextrin, polyalditol, hyaluronic acid, dextran, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran, dextran sulfate, polysulfate pentosan, And contains chitosan. Specific polysaccharides are, for example, low molecular weight polymers with little or no branching as derived and / or found in starch formulations of maltodextrin, amylose, and cyclodextrin. Thus, the natural biodegradable polysaccharide can be a poly (glucopyranose) polymer with little or no branching.

“Amylose” or “amylose polymer” refers to a linear polymer having repeating glucopyranose units linked by α-1,4 bonds. Some amylose polymers can have very little branching (less than approximately 0.5% of the linkages) via α-1,6 linkages, but linear (unbranched) amylose polymers can still be processed The same physical properties are demonstrated. Usually, amylose polymers obtained from plant sources have a molecular weight of less than approximately 1 × 10 ⁶ Da. Amylopectin is a branched polymer with repeating glucopyranose units linked by α-1,4 bonds to form a relatively linear portion. The linear portions are connected together by α-1,6 bonds. Typically, branch point bonds are greater than 1% of total bonds and are generally 4% -5% of total bonds. Usually, amylopectin obtained from a plant source has a molecular weight of 1 × 10 ⁷ Da or more.

  For example, in some aspects, starch formulations with high amylose content, purified amylose, synthetically prepared amylose, or concentrated amylose formulations can be used in the formulation of hydrophobic derivatives of amylose. In the starch source, amylose is usually present with the branched polysaccharide amylopectin. If a mixture of amylose and a high molecular weight precursor is used (such as amylopectin), amylose may be present in the composition in greater amounts than a higher molecular weight precursor. For example, in some aspects, starch formulations with high amylose content, purified amylose, synthetically prepared amylose, or concentrated amylose formulations can be used in the formulation of hydrophobic derivatives of amylose polymers. In some embodiments, the composition comprises amylose in which the amylose content in the polysaccharide mixture is 50% or more, 60% or more, 70% or more, 80% or more, or 85% or more by weight. Contains a mixture of polysaccharides containing. In other embodiments, the composition comprises a mixture of amylose and a polysaccharide comprising amylopectin, wherein the content of amylopectin in the mixture of polysaccharides is 30% or less or 15% or less.

  The amount of amylopectin present in the starch can also be reduced by handling the starch using an amylopectinase that cleaves α-1,6 bonds, branching the amylopectin into amylose.

  The process can be carried out before, during and / or after the processing to derivatize the amylose polymer having pendant groups with a hydrocarbon segment for concentrating the amount of amylose or for purifying amylose.

  Specific molecular weight amylose can be obtained commercially or prepared. For example, synthetic amylose having average molecular masses of 70 kDa, 110 kDa, and 320 kDa can be obtained from Nakano Vinegar Co., Ltd. (Aichi, Japan). The determination of the use of a specific size range of amylose may depend on factors such as the physical properties of the composition (eg, viscosity), the desired biodegradation rate in the implant, and the properties and amounts of the drug substance (API) unknown.

  Purified or concentrated amylose formulations can be obtained commercially or prepared using standard biochemical techniques such as chromatography. In some aspects, high amylose corn starch can be used to prepare hydrophobic derivatives.

  Maltodextrin typically hydrolyzes the starch slurry with a thermostable α-amylase at a temperature of 85-90 ° C. until a desired degree of hydrolysis is reached, followed by α- Produced by inactivation of amylase. Maltodextrin can be purified to the final product by filtration and subsequent spray drying. Maltodextrins are particularly characterized by the glucose equivalent (DE) for the degree of hydrolysis defined as DE = MW glucose / number-average MW starch hydrolyzate × 100. In general, maltodextrins are believed to have a lower molecular weight than amylose molecules.

  Starch formulations fully hydrolyzed to glucose (glucose) have a DE of 100, whereas starch has a DE of nearly zero. A DE greater than 0 and less than 100 is characteristic of the intermediate average molecular weight of the starch hydrolyzate. Maltodextrins are believed to have a DE less than 20. For example, maltodextrins of various molecular weights in the range of about 500 Da to 5000 Da are commercially available (eg, from Carbomer, San Diego, Calif.).

  Another possible type of natural biodegradable polysaccharide is a natural biodegradable non-reducing polysaccharide. Non-reducing polysaccharides provide an inert matrix, thereby improving the stability of drug substances (APIs) such as proteins and enzymes. Non-reducing polysaccharides are linked through their anomeric centers such as trehalose (α-D-glucopyranosyl α-D-glucopyranoside) and sucrose (β-D-fructofuranosyl α-D-glucopyranoside). Two monosaccharides). Examples of non-reducing polysaccharides include polyalditols available from GPC (Muscatine, Iowa). In other aspects, the polysaccharide is a glucopyranosyl polymer, such as a polymer comprising repeating (1 → 3) O-β-D-glucopyranosyl units.

  Dextran is α-D-1,6-glucose bound to a glucan with side chains 1-3 bound to the backbone unit of the dextran biopolymer. Dextran contains hydroxyl groups at the 2, 3, and 4 positions on the glucopyranose monomer unit. Dextran can be obtained from fermentation of a medium containing sucrose by Leuconostoc mesenteroides B512F.

  Dextran can be obtained in low molecular weight formulations. Enzymes from molds (dextranase) such as blue mold and verticillium have been shown to degrade dextran. Similarly, many bacteria produce an extracellular dextranase that degrades dexton to low molecular weight carbohydrates.

  Chondroitin sulfate contains repeating disaccharide units of D-galactosamine and D-glucuronic acid, and is generally contained between 15 and 150 of these repeating units. Chondroitinase AC cleaves chondroitin sulfates A and C, and chondroitin.

  Hyaluronic acid (HA) is a naturally derived linear polymer containing alternating β-1,4-glucuronic acid and β-1,3-N-acetyl-D-glucosamine units. HA is the main glycosaminoglycan in the connective tissue fluid. HA can be subdivided in the presence of hyaluronidase.

  In many aspects, the polysaccharide portion and the hydrophobic portion comprise a major portion of a hydrophobic derivative of a natural biodegradable polysaccharide. Based on the weight percentage, the polysaccharide moiety is about 25% mass or more of the hydrophobic derivative, in the range of about 25% to about 75%, in the range of about 30% to about 70%, in the range of about 35% to about 65%. , Approximately 40% to approximately 60%, or approximately 45% to approximately 55%. Similarly, based on the weight percentage of the total hydrophobic derivative, the hydrophobic moiety is approximately 25% mass or more of the hydrophobic derivative, in the range of approximately 25% to approximately 75%, approximately 30% to approximately 70%. It can be in the range of approximately 35% to approximately 65%, approximately 40% to approximately 60%, or approximately 45% to approximately 55%. In one example, the hydrophobic derivative has approximately 50% mass-derived for the polysaccharide moiety and approximately 50% mass-induced for the hydrophobic moiety.

  Hydrophobic derivatives have the property of being insoluble in water. The term insoluble is a standard term in the art and means 1 part of solute per 10,000 parts or more of solvent (eg Remington: The Science and Practice of Pharmacy, 20th ed. (2000), Lippincott Williams & Wilkins, Baltimore Md.).

  Hydrophobic derivatives can be prepared by conjugating one or more hydrophobic compounds having a natural biodegradable polysaccharide polymer. Methods for preparing hydrophobic derivatives of natural biodegradable polysaccharides are described herein.

  Hydrophobic derivatives of natural biodegradable polysaccharides specifically have an average molecular weight of up to about 1,000,000 Da, up to about 300,000 Da, or up to about 100,000 Da. The use of these molecular weight derivatives can provide implants with the desired physical and drug release properties. In some aspects, the hydrophobic derivative has a molecular weight of about 250,000 Da or less, about 100,000 Da or less, about 50,000 Da or less, or about 25,000 Da or less. In particular, specific size ranges for natural biodegradable polysaccharides are in the range of about 2,000 Da to about 20,000 Da, or about 4,000 Da to about 10,000 Da.

The molecular weight of the polymer is defined in more detail as “mass average molecular weight” or M _w . M _w is an absolute method of molecular weight measurement, and is particularly useful for measurement of molecular weight (formulation) of a polymer. Polymer formulations typically include polymers that have individually small differences in molecular weight. A polymer is a molecule having a relatively high molecular weight, and such small differences within a polymer formulation do not affect the overall properties of the polymer formulation. M _w can be measured using common techniques such as light scattering or ultracentrifugation. Considerations for _Mw and other terms used to define the molecular weight of polymer formulations are described in, for example, Allcock, H .; R. And Lampe, F.A. W. (1990) Contemporary Polymer Chemistry; pg 271.

  The addition of a hydrophobic moiety generally causes an increase in the molecular weight of the polysaccharide from the non-derivatized product. The amount of increase in molecular weight is one or more factors including the type of derivatized polysaccharide, the level of induction, and the type, for example, the type of group attached to the polysaccharide to provide a hydrophobic moiety. It can be up to you.

  In some aspects, the addition of a hydrophobic moiety causes an increase in the molecular weight of the polysaccharide by about 20% or more, about 50% or more, about 75% or more, about 100% or more, or about 125%. Relates to the non-derivatized form of polysaccharides.

  As an example, a maltodextrin having an initial mass of about 3000 Da is derived to provide a pendant hexanoate group that is linked to the polysaccharide by an ester bond to provide a degree of substitution (DS) of about 2.5. . This provides a hydrophobic polysaccharide with a theoretical molecular weight of approximately 8400 Da.

  By way of example, when forming a hydrophobic derivative of a natural biodegradable polysaccharide, a compound having a hydrocarbon segment is covalently bound to one or more moieties of the polysaccharide. For example, the compound can be linked to monomer units along the length of the polysaccharide. This provides a polysaccharide derivative having one or more pendant groups. Each chemical group contains a hydrocarbon segment. The hydrocarbon segment may constitute all of the pendant chemical groups, or the hydrocarbon segment may constitute some portion of the pendant chemical groups. For example, a portion of the hydrophobic polysaccharide can have the following structural chemical formula (I):

  Where each M is an independent monosaccharide unit, each L is an independent suitable linking group or direct bond, each PG is an independent pendant group, and each x is When x is 0, L and M are about 0 to about 3 so that they are absent, and y is 3 or more.

  Further, the polysaccharide comprising the unit of formula (I) may be a compound of formula (II):

Where each M is an independent monosaccharide unit, each L is an independent suitable linking group or direct bond, each PG is an independent pendant group, and each x is When x is 0, L and M are independent 0 to about 3, such that they are absent, y is about 3 to about 5000, and Z ¹ and Z ² are each independently hydrogen, OR ¹ , _{^{OC (= O) R 1,}} CH 2 oR 1, SiR 1 or _CH 2 OC (= O) is ^{R 1.} Each R ¹ is an independent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heteroaryl, each alkyl, cycloalkyl, aryl, heterocycle and heteroaryl is optionally substituted And alkyl, cycloalkyl, and heterocycle are optionally partially unsaturated.

  In the compounds of formula (I) and (II), the monosaccharide unit (M) may comprise D-glucopyranose (eg α-D-glucopyranose). In addition, the monosaccharide unit (M) is composed of non-macrocyclic poly α (1 → 4) glucopyranose, non-macrocyclic poly α (1 → 6) glucopyranose, or non-macrocyclic poly α (1 → 4). ) A mixture of glucopyranose and non-macrocyclic poly alpha (1 → 6) glucopyranose or a combination of both. For example, the monosaccharide unit (M) can comprise glucopyranose units, and at least about 90% can be linked by α (1 → 4) glycosidic bonds. Alternatively, the monosaccharide unit (M) can comprise glucopyranose units, with at least approximately 90% being bound by α (1 → 6) glycosidic bonds. Moreover, each of the monosaccharides in the polysaccharide may be of the same type (homopolysaccharide), or the monosaccharides in the polysaccharide may be different (heteropolysaccharide).

  The polysaccharide may comprise up to about 5000 monosaccharide units (ie, y in formula (I) or (II) is up to 5000). In particular, the monosaccharide unit can be a glucopyranose unit (eg, an α-D-glucopyranose unit). Further, y in formula (I) or (II) may specifically be about 3-5000 or about 3-4000 or about 100 to 4000.

  In a specific embodiment, the polysaccharide is non-macrocyclic. In other specific embodiments, the polysaccharide is linear. In other specific embodiments, the polysaccharide is branched. Moreover, in a more specific embodiment, the polysaccharide is a natural polysaccharide (PS).

  The polysaccharide will have a suitable glass transition temperature (Tg). In one embodiment, the polysaccharide will have a glass transition temperature (Tg) of at least about 35 ° C. (eg, from about 40 ° C. to about 150 ° C.). In one embodiment, the polysaccharide will have a glass transition temperature from -30 ° C to about 0 ° C.

“Pendant group” refers to a group of covalently bonded carbon atoms having the chemical formula (CH _n ) _m . Here, m is 2 or more, and n is independently 2 or 1. The hydrocarbon segment can include saturated or unsaturated hydrocarbon groups, and examples of such hydrocarbon segments include alkyl, alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, aromatic hydrocarbon, and aralkyl groups. Yes. In particular, pendant groups include linear, straight chain, or branched C ₁ -C ₂₀ alkyl groups; amine-terminated hydrocarbons or hydroxyl-terminated hydrocarbons. In one embodiment, the pendant group comprises a polylactide, polyglycolide, poly (lactide-co-glycolide) copolymer, polycaprolactone, poly (lactide-co-glycolide-co-caprolactone) terpolymer or combinations thereof It is out.

  The hydrophobic polysaccharide monomer units described herein typically include monomer units having a cyclic structure with one or more reactive groups. These reactive groups are exemplified by hydroxyl groups such as those present on glucopyranose based on monomer units, such as amylose and maltodextrin. These hydroxyl groups can be reacted with compounds that contain hydrocarbon segments and groups that react with hydroxyl groups (hydroxyl reactive groups).

  Examples of hydroxyl reactive groups include acetals, carboxyls, anhydrides, acid halides and the like. These groups can be used to form a covalent bond between the hydrocarbon segment and the polysaccharide backbone that can be cleaved by hydrolysis. For example, the method can provide a pendant group having a hydrocarbon segment. The pendant group is attached to a polysaccharide backbone with an ester bond that can be cleaved. In these aspects, synthetic hydrophobic derivatives of natural biodegradable polysaccharides are cleavable enzymatically (polymer backbone) and non-enzymatically cleavable (bonding between pendant groups and polymer backbone). Both chemical bonds may be included.

  Other cleavable chemical bonds that can be used to attach pendant groups to polysaccharides (eg, covalently cleavable covalent bonds) include carboxylic acid ester, carbonate, borate, silyl ether, peroxyester groups Contains disulfide groups and hydrazone groups.

  In some cases, hydroxyl reactive groups include groups such as isocyanates and epoxies. These groups can be used to form a non-cleavable covalent bond between the pendant group and the polysaccharide backbone. In these aspects, the synthesized hydrophobic derivative of the natural biodegradable polysaccharide contains a chemical bond that is cleavable by an enzyme.

  Other reactive groups such as carboxyl groups, acetyl groups, or sulfate groups are present on the cyclic structure of monomer units in other natural biodegradable polysaccharides such as chondroitin or hyaluronic acid. Similarly, these groups can be targets for reaction with compounds having a hydrocarbon segment to be attached to the polysaccharide backbone.

  Various factors can take into account the synthesis of hydrophobic derivatives of natural biodegradable polysaccharides. These factors are: (1) the size of the polysaccharide, the number and presence of reactive groups on the polysaccharide, and the physical and chemical properties of the natural biodegradable polysaccharide, including solubility; (2) the size Including the physical and chemical properties of the compound containing the hydrocarbon segment, including the length and solubility, and (3) the reactivity of the compound with the polysaccharide.

  Any suitable synthetic step can be performed in the preparation of the hydrophobic derivative of the natural biodegradable polysaccharide. The synthesis can be performed to provide the desired number of groups with hydrocarbon segments pendent from the polysaccharide backbone. The number and / or density of pendant groups can be controlled, for example, by controlling the relative concentration of the compound comprising hydrocarbon segments relative to reactive groups (eg, hydroxyl groups) available on the polysaccharide.

  The type and amount of groups having hydrocarbon segments protruding from the polysaccharide are sufficient to make the hydrophobic polysaccharide insoluble in water. To achieve this, as a general method, hydrophobic polysaccharides are hydrocarbons protruding from the polysaccharide backbone in amounts ranging from 0.25 (pendant group): 1 (polysaccharide monomer) by mass. Obtained and prepared in groups with segments.

  The load distribution ratio of glucopyranose units to pendant groups can vary, but typically will be from about 1: 1 to about 100: 1. Specifically, the load distribution ratio of the glucopyranose unit to the pendant group can be about 1: 1 to about 75: 1, or about 1: 1 to about 50: 1. Furthermore, the nature and amount of the pendant group provides the appropriate degree of substitution of the polysaccharide. Typically, the degree of substitution will be in the range of about 0.1-5, or about 0.5-2.

  To demonstrate these levels of derivation, very low molecular weight (less than 10,000 Da) glucopyranose polymers react with compounds with hydrocarbon segments to provide low molecular weight hydrophobic glucopyranose polymers. In one embodiment, the natural biodegradable polysaccharide maltodextrin in an amount of 10 g (MW 3000-5000 Da; ˜3 mmol) is dissolved in a suitable solvent, such as tetrahydrofuran. Next, the maltodextrin solvent is added to the solvent having butyric anhydride in an amount of 18 g (0.11 mol). The above reaction can effectively perform a treatment to form a pendant butyrate group on the pyranose ring of the maltodextrin polymer. This level of derivation results in a degree of substitution (DS) of butyrate base at the hydroxyl group on maltodextrin of about 1.

  For maltodextrins and other polysaccharides containing three hydroxyl groups per monomer unit, on average one of the three hydroxyl groups per glycopyranose monomer unit is replaced with a butyrate base. A maltodextrin polymer having this level of substitution is referred to herein as maltodextrin-butyrate DS1. As described herein, DS is the reactive group per monomer unit (including hydroxyl and other reactive groups), which is the average number of reactive groups that are substituted with pendant groups containing hydrocarbon segments. Show.

  The increase in DS can be achieved by an additional increase in the amount of compound that provides the hydrocarbon segment to the polysaccharide. As another example, a butyrylated maltodextrin with a DS of 2.5 was prepared by reaction of 10 g maltodextrin (MW 3000-5000 Da; ˜3 mmol) with 0.32 moles of butyric anhydride. sell.

  The degree of substitution can affect the hydrophobic properties of the polysaccharide. Similarly, implants formed from hydrophobic derivatives having a substantial amount of groups with hydrocarbon segments attached to a polysaccharide backbone (such as high DS) are usually more hydrophobic and more resistant to degradation There is. For example, an implant formed from maltodextrin-butyrate DS1 has a faster degradation rate than an implant formed from maltodextrin-butyrate DS2.

The type of hydrocarbon segment of the group protruding from the polysaccharide backbone can also affect the hydrophobic properties of the polymer. In one form, the implant is formed by using a hydrophobic polysaccharide with a pendant group with a hydrocarbon segment that is a short-chain branched alkyl group. An example of a short-chain branched alkyl group is a branched C ₄ -C ₁₀ group. The preparation of hydrophobic polymers with these types of pendant groups is demonstrated by the reaction of maltodextrin with valproic acid / anhydride with maltodextrin (MD-val). The above reaction can be performed to provide a relatively low degree of substitution of the hydroxyl group (eg in the range of 0.5-1.5). Although these polysaccharides have a low degree of substitution, the short chain branched alkyl group imparts hydrophobic properties to the polysaccharide.

Even with these low degrees of substitution, MD-val forms very compliant and durable coatings. Due to the low degree of substitution, pendant groups with branched C ₈ segments can be hydrolyzed from the polysaccharide backbone at a relatively fast rate. The result is a biodegradable coating with a relatively fast degradation rate.

  For polysaccharides with pendant groups that contain hydrocarbon segments and are cleavable by hydrolysis, penetration by aqueous solution promotes hydrolysis and loss of groups protruding from the polysaccharide backbone. sell. This can alter the properties of the implant and can result in more utilization of enzymes that promote the degradation of natural biodegradable polysaccharides.

  Various synthetic schemes can be used for the preparation of hydrophobic derivatives of natural biodegradable polysaccharides. In some preparative aspects, the pendant polysaccharide hydroxyl group reacts with a compound that includes a hydrocarbon segment and a group that reacts with the hydroxyl group. This reaction can result in a polysaccharide having pendant groups that make up the hydrocarbon segment.

  Any suitable chemical group can be attached to the polysaccharide backbone and result in a polysaccharide having hydrophobic properties when the polysaccharide is insoluble in water. Specifically, the pendant group may include one or more atoms selected from carbon (C), hydrogen (H), oxygen (O), nitrogen (N), and sulfur (S).

In some embodiments, the pendant group may be linear, it includes a hydrocarbon segment is a branched or cyclic C ₂ -C ₁₈ group. More specifically, the hydrocarbon _segments, C 2 _{-C 10} or _C 4 -C ₈ linear, contains branched, or cyclic group. The hydrocarbon segment can be saturated or unsaturated and can contain an alkyl group or an aromatic group, respectively. The hydrocarbon segment can be linked to the polysaccharide chain via a hydrolyzable bond or a non-hydrolyzable bond.

  In some embodiments, the compound having a hydrocarbon segment that reacts with the polysaccharide backbone is derived from a natural compound. Natural compounds having a hydrocarbon segment include fatty acids, lipids, oils, waxes, phospholipids, prostaglandins, thromboxanes, leukotrienes, terpenes, steroids and fat-soluble vitamins.

  Typical natural compounds having a hydrocarbon segment include fatty acids and their derivatives such as fatty acid anhydrides and fatty acid halides. Typical fatty acids and anhydrides include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid, caprylic acid, capric acid and lauric acid, and anhydride, respectively. The hydroxyl group of the polysaccharide can react with a fatty acid or an anhydride to link the hydrocarbon segment of the compound and the polysaccharide via an ester group.

  The hydroxyl group of the polysaccharide can also cause ring opening of the lactone to yield a pendant open chain hydroxy ester. Typical lactones that can react with polysaccharides include caprolactone and glycolide.

In general, if compounds with multiple hydrocarbon segments are used in the synthesis of hydrophobic derivatives, small amounts of compounds may be required for their synthesis. For example, in principle, when used to compounds having a hydrocarbon segment having an alkyl chain length of C _x to prepare a hydrophobic derivative of one DS, hydrocarbon segment with C _{(x × 2)} alkyl chain length The compound having a reacts with an amount to give a hydrophobic derivative of DS of 0.5.

  Hydrophobic derivatives of natural biodegradable polysaccharides can likewise be synthesized each having a combination of pendant groups having two or more different hydrocarbon segments. For example, hydrophobic derivatives can be synthesized using compounds having hydrocarbon segments with different alkyl chain lengths. In an embodiment of the embodiment, the polysaccharide is selected from two groups selected from the group of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid, caprylic acid, capric acid and lauric acid to produce a hydrophobic derivative. Reacts with mixtures of the above fatty acids (or their derivatives).

  In another case, the hydrophobic derivative is synthesized with a non-hydrolyzable bond where the hydrocarbon segment is attached to the polysaccharide backbone. Typical non-hydrolyzable bonds include urethane bonds.

  Alternatively, hydrophobic derivatives of natural biodegradable polysaccharides can be synthesized such that the hydrocarbon segments are individually attached to the polysaccharide backbone through both hydrolyzable and non-hydrolyzable bonds. . As another example, hydrophobic derivatives are prepared by reaction of a mixture of butyl isocyanate with butyric anhydride and maltodextrin. This results in a hydrophobic derivative of maltodextrin having pendant butyric acid groups individually covalently bonded to the maltodextrin backbone having hydrolyzable ester linkages and non-hydrolyzable urethane linkages. Degradation of coatings with this type of hydrophobic derivative can occur due to the loss of butyrate base from hydrolysis of the ester bond. However, some butyrate bases (those linked via a urethane group) are not removed from the polysaccharide backbone, and therefore natural biodegradable polysaccharides are not prior to enzymatic degradation of the polysaccharide backbone. The desired degree of hydrophobicity can be retained.

  In some embodiments, the group protruding from the polysaccharide backbone has the properties of an API (API). In this regard, the implant includes a polysaccharide linked to an API. In some embodiments, an API having a hydrocarbon segment can be hydrolyzed from a natural biodegradable polymer. It can then be released from the matrix to provide a therapeutic effect. One example of a compound that has a hydrocarbon segment and is useful as a treatment is butyric acid, which has been shown to induce tumor cell differentiation and apoptosis, and treats cancer and other blood diseases It is considered useful for.

  Other representative hydrocarbon segment containing compounds include valproic acid and retinoic acid. These compounds can be coupled to the polysaccharide backbone to provide pendant groups. And then, it is cleaved from the polysaccharide backbone in the degradation of the implant in vivo. Retinoic acid is known to have an antiproliferative effect and is believed to be useful in the treatment of proliferative vitreoretinopathy (PVR). Pendant groups that provide a therapeutic effect can also be natural compounds such as butyric acid, valproic acid and retinoic acid.

  Another representative class of compounds that can be coupled to the polysaccharide backbone is corticosteroids. An example of a corticosteroid is triamcinolone. One method of coupling triamcinolone with natural biodegradable polymers is described in Cayanis, E. et al., “Generation of an Auto-anti-idiotypic Antibody that Binds to Glucocorticoid Receptor, The Journal of Biol. Chem., 261 (11). : 5094-5103 (1986) ". Triamcinolone hexanoic acid reacts triamcinolone with ketohexanoic acid to form the acid chloride of the resulting triamcinolone hexanoic acid and reacts with a natural biodegradable polymer such as, for example, maltodextrin or polyalditol, Prepared by providing pendant triamcinolone groups attached to the natural biodegradable polymer via an ester linkage.

  Hydrophobic derivatives of natural biodegradable polysaccharides can also be synthesized with two or more different pendant groups while at least one pendant group contains an API. Hydrophobic polysaccharides can be synthesized while the amount of pendant groups, including API, provides a therapeutic effect on the subject when released from the polysaccharide. An example of such a hydrophobic derivative is maltodextrin-capron hydrochloride-triamcinolone. This hydrophobic derivative is obtained by reaction of a mixture containing triamcinolone hexanoic acid and excess caproic anhydride (n-hexane anhydride) with maltodextrin to provide a derivative with a DS of 2.5. Can be prepared.

  In some embodiments, the group protruding from the polysaccharide includes a hydrocarbon segment that is an aromatic group such as, for example, a phenyl group. As an example, o-acetylsalicylic acid provides a pendant chemical group with a hydrocarbon segment that is a phenyl group and a non-hydrocarbon segment that is an acetate base while the pendant group is attached to the polysaccharide via an ester bond. Reacts with polysaccharides such as maltodextrin.

  Additional features and types of biodegradable polymers, including hydrophobic derivatives of natural biodegradable polysaccharides (referred to as Eureka ™ SOLO polymers) are described in, for example, US 2007/0218102, US 2007/02600054. And in US 2007/0224247 and references cited therein.

As an example of coating application, the biodegradable coating in the expandable and foldable structure 12 is generated by preparing a coating composition that includes a biodegradable multi-block copolymer, and the structure (eg, balloon ) By spraying the solution onto (with or without hydrogel base coat). The biodegradable multiblock copolymer includes glycolic acid, caprolactone, and PEG polymer block dissolved in 30 mg / mL acetone. The bioactive agent (eg, in the form of a bioactive agent) can be applied after the coating solution (1-50% by weight) is dissolved or a degradable coating is formed. For example, paclitaxel (dissolved in methanol or present as a bioactive agent in water) can be applied to the biodegradable coating.

  The coating composition used to form the biodegradable coating can include one or more additional biocompatible polymers. For example, a second, third, etc. biocompatible polymer can be included in the coating composition to form a coating having the desired properties. One or more additional polymers can increase the degradation of the coating. In some embodiments, the biodegradable polymer comprises, for example, a biodegradable polymer such as polylactide and a group consisting of, for example, poly (ethylene glycol) (PEG), poly (ethylene oxide), and poly (propylene oxide). Formed from a biocompatible polymer, such as those selected.

  Various methods can be implemented to combine the polymeric material and the bioactive agent on the surface of the expandable and foldable structure. In many embodiments, a coating composition comprising a polymeric material and a bioactive agent is prepared and then applied to the surface of the expandable and foldable structure. In one embodiment, a coating composition comprising a bioactive agent at a concentration in the range of about 10 mg / mL to about 50 mg / mL is used.

  However, the polymeric material may be applied to the surface separately from the bioactive agent. For example, in a first step, a polymer composition is applied to the surface, and in a second step, a composition having a bioactive agent (without polymer coating material) is applied to the pre-coated polymer. In one embodiment, a composition having a concentration of bioactive agent in the range of about 10 mg / mL to about 50 mg / mL (excluding polymer coating material) is used. In addition, optionally, the steps can be performed to apply to the same or other polymeric material, such as a top coat covering the bioactive agent.

  In one preferred form, the coating is formed on the surface of the expandable and foldable structure using a spray coating process. In certain embodiments, the balloon catheter is attached to a device that can manipulate the balloon for coating using a spray deposition process.

  Further embodiments and details of the balloon coating apparatus and method are described in provisional application 61 / 188,929 with the same applicant (Filing date: August 14, 2008, Title of invention: METHOD AND APPARATUS FOR COATING BALLOON CATHETERS (Chappa et al.), The disclosure of which is incorporated herein by reference.

  Alternatively, the coating composition is dip coated onto the surface of the expandable and foldable structure to form a coated surface. In other methods, the composition is brushed onto the surface of the expandable and foldable structure. In some applications, the substrate can undergo one or more steps of coating a mixture of polymeric material and bioactive agent to form multiple layers on the substrate surface.

  In one form, the coating is prepared by processing a coating material disposed on the expandable and foldable structure. For example, the coating composition can include reactive groups that when activated cause cross-linking of the polymeric material to form a coating. The polymeric material used to form the coating can include pendent polymerizable groups such as acrylate groups. Radical polymerization of a polymerizable group can be caused by activation of a photoactivatable reagent that is a polymerization initiator. The applied composition can be subjected to UV treatment to activate the polymerization initiator.

  Using various techniques, the particles of bioactive agent can be combined with a coating to provide partially embedded particles. In one technique, a flexible hydrogel layer is formed on the surface of the expandable and foldable structure. Next, the aqueous composition containing the bioactive agent is placed on the surface of the flexible hydrogel layer. Water in the aqueous composition causes at least the surface of the flexible hydrogel layer to swell. This expansion causes the flexible hydrogel layer to permeate at least a portion of the bioactive agent disposed in the hydrogel layer, and the bioactive agent migrates into the polymer material of the hydrogel layer. After sufficient time has passed to partially transfer the bioactive agent to the hydrogel layer, the water can be removed by evaporation, heating or vacuum treatment. The removal of water causes the hydrogel layer to contract from the expanded state and physically restrains the bioactive agent. The result is that most of the bioactive agent disposed on the surface of the hydrogel layer is partially embedded.

  4 and 5, the catheter assembly covering 32 has an optional release coating 35 disposed on one surface of the outer surface 22 of the expandable and foldable structure 12. It is shown. In the depicted embodiment, the optional free dressing 35 is disposed between the outer surface 22 and the drug coating 34. In some embodiments, the optional free dressing 35 need not occupy the entire area between the drug coating 34 and the expandable and foldable structure 12.

  The optional free coating material 35 may be present on the expandable and foldable structure 12 and may facilitate the release of a coating containing a bioactive agent (drug coating) from the structure at the target site. A free coating material 35 may be present between the drug coating 34 and the expandable and foldable structure 12. The free coating material 35 can be configured to facilitate the release of the drug coating 34 at a target site within the subject. For example, the free coating material 35 can expand and push the drug containing the coating. In one embodiment, the free coating material 35 is crushed by pressing the drug containing the coating. In one embodiment, the free dressing material comprises a polymer that swells with water or is made of a polymer that swells with water that rapidly absorbs water. Upon exposure to blood, water wicks into the layer, reducing adhesion between the release layer and the drug coating.

  Referring to FIG. 6, the covering 32 of the catheter assembly 10 is shown having an optional protective layer 36 disposed on one side of the drug covering 34. In one embodiment, the optional protective layer 36 is a lipid coating. In some embodiments, the protective layer 36 need not cover all of the drug coating 34.

  The lipid coating may provide one or more of several advantageous features for the catheter assembly 10. The lipid coating may, for example, 1) protect the underlying coating containing a bioactive agent (eg, drug coating), 2) a lubricant (eg, sacrificial lubrication) when the subject's tissue contacts the device. 3) resulting in a variable hydrophobic matrix that further enhances delivery to hydrophobic tissues or their surfaces (eg, the walls of blood vessels) 4) assembled under the coating and bioactive agent ( It can result in a matrix that retains structural integrity (eg, held together) or one or more of these features.

  In one embodiment, the lipid dressing is solid (eg, waxy) or semi-solid at room temperature and soft or liquid at the body temperature of the subject. For example, the lipid dressing is a solid that is solid at room temperature and liquid at 37 ° C., or may be a lipid or mixture of lipids, or a coating that protects an underlying coating that contains a bioactive agent. Form. A mixture of 50% by weight oleic acid and 50% by weight dodecanoic acid is such a coating composition. In one embodiment, the lipid dressing can increase the amount of bioactive agent delivered to the tissue after the balloon catheter is passed through a tortuous path.

  In one embodiment, the lipid dressing is solid at room temperature but softens or melts (eg, liquefies) when exposed to the body temperature of the subject. In one embodiment, the barrier layer is solid at room temperature, but is soft when the coated portion of the device directs its path through the subject to a position where the bioactive agent is delivered (delivery position). Become or melt. For example, the barrier layer comprises or comprises a composition having a melting point or softening point above room temperature and below the subject's body temperature. This softening or melting can occur when the coated part of the device orients its path towards the delivery position. Alternatively, this softening or melting can occur at the delivery position. Or it can happen in both. A softened, softened, melted, or melted lipid composition when the coated portion of the device has its path directed to the delivery position, the delivery position, or both The catheter assembly 10, the portion of the catheter assembly 10 with the coating containing the bioactive agent, or both can be left intact.

  In one embodiment, the lipid dressing can increase the amount of bioactive agent delivered to the desired location within the subject when the catheter assembly 10 is inserted into the subject. For example, a solid or semi-solid lipid coating can be applied to the exterior of a subject when the coated portion of the device directs its path through the subject to a location where bioactive agent is delivered. While handling the catheter assembly 10, the coating containing the bioactive agent can be protected and / or separated. That is, a solid or semi-solid lipid coating is used to treat the coating containing the bioactive agent by air, by treatment, before the coated portion of the device reaches the location where the bioactive agent is to be delivered. The degree of contact can be reduced by a guide catheter or other medical device, by tissue, by bodily fluids, or more. This reduced contact can increase the amount of bioactive agent delivered to the desired location. Such lipid coatings protect the underlying drug coating.

  In one embodiment, the lipid dressing increases the ease or reduces resistance associated with the catheter assembly 10 having its path in the direction to the delivery position, eg, through the guide catheter. For example, a solid or semi-solid lipid coating may be used when the coated portion of the device directs its path through the guide catheter to the location where the bioactive agent is delivered. The device passageway can be lubricated when inserted into the device or both. That is, the solid or semi-solid lipid coating is such that the coating containing the bioactive agent is guided by the guide catheter before the coated portion of the device reaches or is positioned where the bioactive agent is delivered. The degree to which the tissue, body fluid, or both of the subject is contacted or polished / scrubbed can be reduced. Solid or semi-solid lipid coatings can reduce friction from the underlying coating in contact with the device or guide catheter, tissue, or fluid. Such lubrication can result in an increase in the amount of bioactive agent delivered to the desired location. As the catheter assembly 10 orients its path to the delivery position, the lipid coating is removed from the device for smoothing. That is, the lipid coating can be a sacrificial lubricant.

  In one embodiment, the lipid coating is in contact with the bioactive agent and the subject's tissue to assist in delivering the drug to the tissue. The subject's tissue has a degree of hydrophobicity and is closer to the lipid coating composition than a matrix finished with bodily fluids or drug coatings. The hydrophobicity of the lipid coating can aid in absorption or adsorption of bioactive agents within or on the subject's tissue. In one embodiment, the bioactive agent will be present in the lipid composition (eg, degraded or dispersed) when in the delivery position. The lipid coating material adheres to the subject's tissue, and can likewise adhere to the bioactive agent (eg, in the form of microparticles) and to the subject's tissue. Such absorption, adsorption, or adhesion can result in an increase in the amount of bioactive agent delivered to the desired location.

  In one embodiment, the lipid coating enhances the structural integrity of the coating and bioactive agent on the device. For example, solid or semi-solid lipid coatings can be used to remove microparticles of active agents or microparticles of active agents that are removed from the device when the device directs its path toward the delivery position or when the device is manipulated by medical personnel. The occurrence rate of the part can be prevented or reduced. The lipid coating is, for example, a viscous matrix or contact matrix that holds these various coatings and particles together when the catheter assembly 10 directs its path through a tortuous path to a delivery position. Can be regarded as The lipid coating is a viscous matrix that holds these various coatings and particles together when, for example, the catheter assembly 10 contacts its vessel wall or other tissue when its path is in the delivery position. Or it can be regarded as a contact matrix. As the catheter assembly 10 directs its path through the subject to the delivery position, the lipid coating can be removed from the device when protected. That is, the lipid coating material can be handled as a sacrificial protective agent.

Lipid Composition The lipid composition herein may comprise a lipid or a mixture of lipids. The lipid or mixture of lipids is, for example, solid at room temperature (such as wax or glue) or semi-solid and soft or liquid at the body temperature of the subject.

  In one embodiment, the lipid composition includes a lipid having a melting point of 40 ° C. or higher and a lipid having a melting point of 20 ° C. or lower. In one embodiment, the lipid composition includes a lipid having a melting point of 37 ° C. or higher and a lipid having a melting point of 30 ° C. or lower. In one embodiment, the lipid composition comprises a lipid having a melting point of about 35 ° C. to about 45 ° C. and a lipid having a melting point of about 0 ° C. to about 35 ° C.

  The lipids used in the lipid coating are marine oils such as herring, menhaden, pirchard, sardines, whales, or mixtures thereof; soybean oil, cottonseed oil, corn oil, peanut oil, sunflower oil, Contains safflower oil, olive oil, coconut oil, or mixtures thereof; or mixtures thereof. The lipid composition can be a mixture of lipids that are liquid at room temperature and lipids that are solid at room temperature. Lipids that are liquid at room temperature are sold under the trade name High Oleic CV-65 canola oil (Cargill Inc., Minnetonka, Minn.). In one embodiment, an oil that is liquid at room temperature is not hydrogenated (eg, neither partially hydrogenated nor fully hydrogenated). In one embodiment, the lipid that is solid at room temperature is a partially or fully hydrogenated oil, such as a fully hydrogenated oil. Lipids that are liquid at room temperature are sold under the trade name STABLE FLAKE C® and are cottonseed stearin products (C. & T. Refinery, Inc. of Richmond, Va.).

  In certain embodiments, the lipid composition is an oil such as, for example, vegetable oil, floral essential oil, animal oil, marine oil (eg, fish oil), tropical oil (eg, coconut oil or coconut oil), olive oil, peanut oil; Fats, milk fats; saturated fatty acids such as butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid or mixtures thereof; eg octadecanetrienoic acid, eicosanoic acid, eicosene Acids, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, behenic acid, erucic acid, lignoceric acid, etc. Unsaturated fatty acids; such as phosphatidylglycerol, phosphatidic acid, Natural or synthetic phospholipids such as sphatidylcholine, cardiolipin, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, dimyristolphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine; mono-, di-or Triacylglycerols or mixtures thereof can be included. Pork fat purifies, purifies, and melts pork fat at approximately 86 ° F. (30 ° C.).

  In certain embodiments, the lipid composition present comprises one or more fats, waxes, sterols, phospholipids; mono-, di- or tri-glycerides; fatty acyls, glycerolipids, glycerophospholipids, sphingolipids (eg, sphingomyelin ), Glycolipid (saccharolipid), polyketide, sterol lipid, prenol lipid, or mixtures thereof. Further suitable lipids include ceramides, phosphosphingolipids, glycosphingolipids containing fatty acid moieties saturated or monounsaturated with carbon atoms of 16 to 26 chain lengths.

  The melting point of the lipid composition present can be determined by any one of a number of methods accepted in the art. Suitable methods are included in the Mettler drop point test (see, eg, ASTM D 3954). That is, in this test, the measured sample is placed in a cup and warmed at the desired rate. The temperature at which the drop of molten material passes through the standard opening is recorded. Other methods include AOCS Method Cc 2-38 (Wiley melting point), open capillary slip point, and softening point test.

  Useful methods of making lipid compositions that are solid at room temperature and components of these compositions or appear in this way are described in US Pat. No. 6,544,579, the disclosure of which Which is incorporated herein by reference. The lipid composition can be cooled to ambient temperature or supercooled to provide a lipid coating.

  In one embodiment, the lipid composition consists essentially of one or more lipids. In one embodiment, the lipid composition consists of one or more lipids. Lipids are generally not active agents.

Fatty Acids The lipid composition may comprise one or more fatty acids, free fatty acids that are not esterified, or fatty acids that have been derivatized in other ways. The fatty acid can include or be a carboxylate (eg, a fatty acid salt). Suitable fatty acids include saturated and unsaturated fatty acids. Suitable unsaturated fatty acids include monounsaturated fatty acids and polyunsaturated fatty acids. In one embodiment, the fatty acid composition includes monounsaturated fatty acids. In one embodiment, the fatty acid composition includes a saturated fatty acid. In one embodiment, the fatty acid composition includes saturated fatty acids and monounsaturated fatty acids.

Suitable saturated fatty acids contain 6 to 28 carbon atoms. In one embodiment, the chemical formula of the saturated fatty acid is CH ₃ (CH ₂ ) _n COOH, where 4 ≦ n ≦ 18. In certain embodiments, n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In some embodiments, 6 ≦ n ≦ 8, 8 ≦ n ≦ 16, or 10 ≦ n ≦ 14. In one embodiment, n is 10.

Suitable unsaturated fatty acids contain 8 to 24 carbon atoms. In one embodiment, the formula of the unsaturated fatty acid is CH ₃ (CH ₂ ) _m C═CH (CH ₂ ) _o COOH, and m and o are independently 2 or more and 18 or less. In certain embodiments, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18. In certain embodiments, o is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18. In some embodiments, 4 ≦ m ≦ 18, 6 ≦ m ≦ 14, or 6 ≦ m ≦ 8. In some embodiments, 4 ≦ o ≦ 18, 6 ≦ o ≦ 14, or 6 ≦ o ≦ 8. In one embodiment, m is 7, o is 11, and the double bond is cis. In one embodiment, the chemical formula of the unsaturated fatty acid is CH ₂ ═CH (CH ₂ ) _p COOH and 3 ≦ p ≦ 21.

  In one embodiment, the unsaturated fatty acid may be described as C: D. Here, C is the number of carbon atoms, and D is the number of double bonds. C can be 6 to 24 and D can be 2 to 6. C and D are integers. In one embodiment, D can be 1 and C can be 6 to 24. Also, the position and spatial arrangement of the double bonds are the default locations.

  In one embodiment, the fatty acid composition includes a saturated fatty acid having a melting point of 30 ° C. or higher and an unsaturated fatty acid having a melting point of 20 ° C. or lower. In one embodiment, the fatty acid composition includes a saturated fatty acid having a melting point of 35 ° C. or higher and an unsaturated fatty acid having a melting point of 35 ° C. or lower. In one embodiment, the fatty acid composition comprises a saturated fatty acid having a melting point of about 30 ° C. to about 45 ° C. and an unsaturated fatty acid having a melting point of about 0 ° C. to about 35 ° C.

  In one embodiment, the lipid coating material comprises or consists of a plurality of fatty acids. The plurality of fatty acids can be two fatty acids. The lipid dressing can be a fatty acid or a mixture of (eg, two) fatty acids. The fatty acid or fatty acids can be a barrier layer or a composition that creates a barrier layer. The plurality of fatty acids can be a mixture of fatty acids that are solid at room temperature and soft or liquid at the body temperature of the subject. The plurality of fatty acids can be a mixture of fatty acids that soften at a temperature above room temperature and below a subject's body temperature. The plurality of fatty acids can be a mixture of fatty acids having a melting point above room temperature and below the body temperature of the subject.

Phospholipid In one embodiment, the lipid composition comprises a phospholipid. Suitable phospholipids include, for example, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or mixtures thereof.

  Suitable phosphatidylcholines are, for example, 1,2-didecanoyl-sn-glycero-3-phosphocholine (CAS no. 3436-44-0), 1,2-dielcoyl-sn-glycero-3-phosphocholine (CAS no. 56649- 39-9), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (CAS no. 998-06-1), 1,2-dilarloyl-sn-glycero-3-phosphocholine (CAS no. 18194-25- 7) 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (CAS no.18194-24-6), 1,2-dioleoyl-sn-glycero-3-phosphocholine (CAS no. 4235-95-4) ), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (CAS no. 63-89-8), phosphatidylcholine purified from egg, phosphatidylcholine purified from soybean, lysophosphatidylcholine, 1-mi Ristoyl-2-palmitoyl-sn-glycero 3-phosphocholine, 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-palmitoyl- 2-oleoyl-sn-glycero-3-phosphocholine (CAS no. 26853-31-6), 1,2-distearoyl-sn-glycero-3-phosphocholine (CAS no. 816-94-4), 1- Palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1-stearoyl -2-palmitoyl-sn-glycero-3-phosphocholine or this It contains a mixture of et.

  Suitable lysophosphatidylcholines are, for example, 1-myristoyl-sn-glycero-3-phosphocholine (CAS no. 18194-24-6), 1-palmitoyl-sn-glycero-3-phosphocholine (CAS no. 17364-16-8) ) 1-stearoyl-sn-glycero-3-phosphocholine (CAS no. 19420-57-6) or a mixture thereof.

  Suitable phosphatidic acids are, for example, 1,2-dielcoyl-sn-glycero-3-phosphate (sodium salt) (CAS no. 80724-31-8), 1,2-dilauroyl-sn-glycero-3- Phosphate (sodium salt), 1,2-dimyristoyl-sn-glycero-3-phosphate (sodium salt) (CAS no. 80724-3), 1,2-dioleoyl-sn-glycero-3-phosphorus Acid salt (sodium salt), 1,2-dipalmitoyl-sn-glycero-3-phosphate (sodium salt) (CAS no. 71065-87-7), 1,2-distearoyl-sn-glycero-3 -Contains phosphate (sodium salt) (CAS no. 108321-18-2) or a mixture of these.

  Suitable phosphatidylethanolamines are, for example, 1,2-dielcoyl-sn-glycero-3-phosphoethanolamine (CAS no. 988-07-2), 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (CAS no. 988-07-2), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl -Sn-glycero-3-phosphoethanolamine (CAS no. 923-61-5), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero -3-Phosphoethanolamine (CAS no. 1069-79-0) or a mixture thereof.

  Suitable phosphatidylserine is, for example, 1,2-dilauroyl-sn-glycero-3-phosphoserine (sodium salt), 1,2-dimyristoyl-sn-glycero-3-phosphoserine (sodium salt), 1,2-di- Palmitoyl-sn-glycero-3-phosphoserine (sodium salt), 1,2-distearoyl-sn-glycero-3-phosphoserine (sodium salt), 1,2-dioleoyl-sn-glycero-3-phosphoserine (sodium salt) (CAS no. 70614-14-1), or a mixture of these.

  Referring to FIG. 7, the covering 32 of the catheter assembly 10 is shown having an optional second protective layer 38 disposed on one side of the protective layer 36. In one embodiment, the optional second protective layer 38 is the same as the protective layer 36. In other embodiments, the optional second protective layer 38 is different from the protective layer 36.

  1 and 2, a sleeve 14 is described. The sleeve 14 is disposed on one surface of the outer surface 22 of the expandable and foldable structure 12. The sleeve 14 is configured to expand from a compressed configuration (shown in FIG. 1) and an expanded configuration (shown in FIG. 14), and is configured to collapse from the expanded configuration to a compressed configuration. ing. The sleeve 14 is configured to protect the covering disposed on the outer surface 22 of the expandable and foldable structure 12 when the catheter assembly 10 is guided along the guidewire 28 to the target site. Yes.

  The sleeve 14 is manufactured from a shape memory alloy. A shape memory alloy can be deformed from its original shape and can return to its original shape from a deformed shape under a specific state (eg, temperature). In the depicted embodiment, the original shape of the sleeve 14 is in a compressed state. When the compressed state is the original shape, the sleeve 14 returns to the compressed state after expansion when the temperature of the sleeve 14 reaches the first temperature. In one embodiment, the first temperature is about normal body temperature (eg, 37 ° C.) or lower. In another embodiment, the first temperature is about normal body temperature or higher.

  In the depicted embodiment, the shape memory alloy of the sleeve 14 is a nickel-titanium (Ni—Ti) alloy (eg, nitinol). In other embodiments, the shape memory alloy is Ni-Ti-X, Cu-Ni-Al, Cu-Zn-Al, Fe-Mn-Si, Ni-Ti-Co, Ni-Cu-X, Ni-Al. Etc.

  The sleeve 14 includes a body 39 having a first axial end 40 and a second axial end 42 disposed on the opposite side. The first axial end 40 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12. On the other hand, the second axial end 42 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12.

  In the depicted embodiment, the body 39 of the sleeve 14 includes a plurality of rails 44 and a plurality of ribs 46. In one embodiment, the body 39 includes at least two rails 44. In other embodiments, the body 39 includes at least four rails 44. In other embodiments, the body 39 includes at least eight rails 44. In other embodiments, the body 39 includes at least twelve rails 44.

  In the embodiment depicted in FIG. 1, the rail 44 typically extends in the left-right direction between the first axial end 40 and the second axial end 42. In FIG. 1, the rail 44 is disposed on the sleeve 14 such that the rail 44 is typically parallel when the sleeve 14 is in a compressed state.

  In the depicted embodiment, each of the rails 44 includes a first end 48 and a second end 50 disposed on the opposite side. The first end 48 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12. On the other hand, the second end 50 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12. In the depicted embodiment, the first ends 48 of adjacent rails 44 are connected to associate. On the other hand, the second end 50 of the rail 44 is connected so as to be associated. In one embodiment, the first end 48 of the adjacent rail 44 is a monolithic structure.

  The rib 46 extends between the rails 44. The rib 46 is configured to support the rail 44. Each rib 46 includes a first end portion 52 and a second end portion 54 disposed on the opposite side. The first end portion 52 is connected to the first rail 44 a of the plurality of rails 44, and the second end portion 54 is connected to the second rail 44 b of the plurality of rails 44. In the depicted embodiment, the first rail 44a and the second rail 44b are directly adjacent. In one embodiment, the rails 44 and ribs 46 are integrated. In other embodiments, the rails 44 and ribs 46 are monolithic structures. In the embodiment depicted in FIG. 1, the ribs 46 are disposed at an inclined angle with respect to the rail 44 when the sleeve 14 is in the expanded state.

  The rails 44 and ribs 46 of the sleeve 14 include an outer surface 55 and an inner surface 56. The inner surface 56 defines a bore 58 in which the expandable and foldable structure 12 is disposed. The rail 44 has a first thickness measured between the outer surface 55 and the inner surface 56, and the rib 46 has a second thickness. In one embodiment, the first thickness and the first thickness are substantially the same. In another embodiment, the first thickness is greater than the second thickness. In one embodiment, the first thickness ranges from about 50 μm to about 1 mm. In other embodiments, the first thickness ranges from about 100 μm to about 200 μm.

  Referring to FIG. 8, an alternative embodiment of the sleeve 60 is shown. The sleeve 60 is disposed over the outer surface 22 of the expandable and foldable structure 12. The sleeve 60 includes a first axial end 62 and a second axial end 64 disposed on the opposite side. The sleeve 60 further includes a plurality of rails 66 and a plurality of ribs 68.

  In the embodiment depicted in FIG. 8, the plurality of rails 66 are disposed between the first axial end 62 and the second axial end 64. Each rail 66 is encased in the outer surface 22 of the expandable and foldable structure 12 such that each rail 66 has a generally annular shape.

  Each rail 66 includes an undulating portion 70. In the depicted embodiment, each rail 66 includes a plurality of undulations 70. The undulating portion 70 is usually a waveform. The undulating portion 70 is configured to decrease when the sleeve 60 expands to the expanded state. In the depicted embodiment, the undulations 70 are sinusoidal in shape.

  Ribs 68 extend between rails 66. In the depicted embodiment, the ribs 68 are typically arranged in the left-right direction. Each rib 68 includes a first end portion 72 and a second end portion 74 disposed on the opposite side. The first end portion 72 is connected to the first rail 66 a of the plurality of rails 66. On the other hand, the second end portion 74 is connected to the second rail 66 b of the plurality of rails 66. In the depicted embodiment, the first rail 66a and the second rail 66b are directly adjacent. In one embodiment, rail 66 and rib 68 are built-in. In other embodiments, the rails 66 and ribs 68 are monolithic structures.

  In the depicted embodiment, the ribs 68 include undulations 76. The undulating portion 76 is configured to expand the rib 68 when the sleeve 60 is expanded. The undulating portion 76 is usually a waveform. In the depicted embodiment, the undulations are sinusoidal in shape.

  Referring to FIG. 9, an alternative embodiment of the sleeve 80 is shown. The sleeve 80 is disposed on the entire outer surface 22 of the expandable and foldable structure 12. The sleeve 80 includes a first axial end 82 and a second axial end 84 disposed on the opposite side. The first axial end 82 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12. On the other hand, the second axial end 84 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12.

  The sleeve 80 further includes a plurality of rails 86 and a plurality of ribs 88. In the embodiment depicted in FIG. 9, the rail 86 typically extends in the left-right direction between the first axial end 82 and the second axial end 84. In FIG. 9, the rail 86 is arranged on the sleeve 80 so that the rail 86 is normally parallel when the sleeve 80 is in a compressed state.

  In the depicted embodiment, each rail 86 includes a first end 90 and a second end 92 disposed on the opposite side. The first end 90 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12. On the other hand, the second end 92 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12.

  Ribs 88 extend between rails 86. In the depicted embodiment, the ribs 88 are arranged in a general direction that is typically perpendicular to the longitudinal axis 20. Each rib 88 includes a first end portion 94 and a second end portion 96 disposed on the opposite side. The first end portion 94 is connected to the first rail 86 a of the plurality of rails 86, and the second end portion 96 is connected to the second rail 86 b of the plurality of rails 86. In the depicted embodiment, the first rail 86a and the second rail 86b are directly adjacent. In one embodiment, the rails 86 and ribs 88 are built-in. In other embodiments, the rails 86 and ribs 88 are monolithic structures.

  In the depicted embodiment, ribs 88 and undulations 98 are included. The undulating portion 98 is configured to expand the rib 88 when the sleeve 80 is expanded. The undulating portion 98 is usually a waveform. In the depicted embodiment, the relief 98 is sinusoidal in shape.

  Referring to FIG. 10, an alternative embodiment of the sleeve 100 is shown. The sleeve 100 is disposed on the entire outer surface 22 of the expandable and foldable structure 12. The sleeve 100 includes a first axial end 102 and a second axial end 104 disposed on the opposite side. The first axial end 102 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12. On the other hand, the second axial end 104 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12.

  The sleeve 100 further includes a plurality of rails 106 and a plurality of ribs 108. In the depicted embodiment, each rail 106 includes a first end 110 and a second end 112 disposed on the opposite side. The first end 110 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12. On the other hand, the second end 112 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12. Each rail 106 is wrapped around an outer surface 22 of the expandable and foldable structure 12 such that each rail 106 spirals about the longitudinal axis 20 of the expandable and foldable structure 12. .

  In the depicted embodiment, each rail 106 includes undulations 116 so that the length of each rail 106 can be expanded when the sleeve 100 is expanded. In the depicted embodiment, each rail 106 includes a plurality of undulations 116. The undulating portion 116 is usually a waveform. The undulating portion 116 is configured to decrease when expanded to the sleeve 100 expanded state. In the depicted embodiment, the undulations 116 are sinusoidal in shape.

  Ribs 108 extend between rails 106. Each rib 108 includes a first end portion 118 and a second end portion 120 disposed on the opposite side. The first end portion 118 is connected to the first rail 106 a of the plurality of rails 106. On the other hand, the second end portion 120 is connected to the second rail 106 b of the plurality of rails 106. In the depicted embodiment, the first rail 106a and the second rail 106b are directly adjacent. In one embodiment, rail 106 and rib 108 are built-in. In other embodiments, the rails 106 and ribs 108 are monolithic structures. In the depicted embodiment, the ribs 108 are typically perpendicular to the rails 106 when the sleeve 100 is in a compressed state.

  In the depicted embodiment, the rib 108 includes a relief 122. The undulating portion 122 is configured to expand the rib 108 when the sleeve 100 expands. The undulating portion 122 is usually a waveform. In the depicted embodiment, the relief 122 is sinusoidal in shape.

  Referring to FIG. 1, the connection of the sleeve 14 and the expandable and foldable structure 12 is described. The sleeve 14 is disposed adjacent to the distal end 16 of the expandable and foldable structure 12 at a first axial end 40 and the expandable and foldable structure 12 at a second axial end 42. Arranged around the expandable and foldable structure 12 to be positioned adjacent the proximal end 18. In one embodiment, the first axial end 40 of the sleeve 14 is secured (eg, glued, secured, fused) to the distal end 16 of the expandable and foldable structure 12. Fastened mechanically, and combinations thereof). On the other hand, the second axial end 42 of the sleeve 14 is not secured from the proximal end 18 of the expandable and foldable structure 12.

  In the embodiment depicted in FIG. 1, the first axial end 40 of the sleeve 14 is mechanically secured to the distal end 16 of the expandable and foldable structure 12. In the embodiment depicted in FIG. 1, the first axial end 40 of the sleeve 14 is mechanically secured to the distal end by a band 130a. The band 130a is crimped around the distal end 16 having the first axial end 40 of the sleeve 14 disposed between the band 130a and the distal end 16 of the expandable and foldable structure 12. Can be done. In another embodiment, the band 130a is a stretch wrap tube structure having an inner diameter that decreases with heating. In other embodiments, the first axial end 40 is adhesively coupled to the distal end 16 of the expandable and foldable structure 12. In other embodiments, the first axial end 40 is mechanically secured and adhesively joined to the distal end 16 of the expandable and foldable structure 12.

  Referring to FIG. 11, the first axial end 40 and the second axial end 42 of the sleeve 14 are secured to the distal end 16 and the proximal end 18 of the expandable and foldable structure 12, respectively. FIG. 2 shows an alternative embodiment of the catheter assembly 10 that has been (eg, glued, secured, fused, mechanically fastened, and combinations thereof). In the embodiment depicted in FIG. 11, the first axial end 40 and the second axial end 42 of the sleeve 14 are the distal end 16 and the proximal end 18 of the expandable and foldable structure 12. Each is fixed mechanically. The first axial end 40 of the sleeve 14 is secured to the distal end 16 by a band 130a, and the second axial end 42 of the sleeve 14 is attached to the proximal end 18 by a second band 130b. It is fixed. In one embodiment, the adhesive is disposed between the band 130 a and the distal end 16 and between the second band 130 b and the proximal end 18.

  Referring to FIG. 12, another embodiment of the catheter assembly 10 is shown. In this embodiment, the first axial end 40 and the second axial end 42 of the sleeve 14 are not secured from the distal end 16 and the proximal end 18 of the expandable and foldable structure 12. . In this embodiment, the inner diameter of the bore 58 of the sleeve 14 when the sleeve 14 is in compression is such that the outer surface 22 of the expandable and foldable structure 12 when the expandable and foldable structure 12 is in the contracted state. Smaller than outer diameter. This interference fit between the expandable and foldable structure 12 and the sleeve 14 holds the sleeve 14 around the expandable and foldable structure 12.

  Referring to FIG. 13, the catheter assembly 10 having a second expandable and foldable structure 140 is shown. The second expandable and foldable structure 140 is disposed adjacent to the proximal end 18 of the expandable and foldable structure 12. The second expandable and foldable structure 140 is configured to expand from a contracted state (shown in FIG. 13) to an expanded state (shown in FIG. 18) and to contract from the expanded state to a contracted state.

The second expandable and foldable structure 140 is configured to reduce or prevent blood flow through blood vessels in the patient's body when the expandable and foldable structure 12 is inflated. The second expandable and foldable structure 140 includes a first end 142, a second end 144 disposed oppositely, and an outer surface 146 that extends between the first end 142 and the second end 144. Is included. In the depicted embodiment, the length L ₁₄₀ of the second expandable and foldable structure ₁₄₀ is such that the expandable and foldable structure 12 and the second expandable and foldable structure 140 are in a contracted state. Sometimes less than the length L _{12 of} the expandable and foldable structure ₁₂ .

  With reference to FIGS. 1, 2, and 13, the plurality of rails 44 and the plurality of ribs 46 in the sleeve 14 define a plurality of openings 150 that extend through the outer surface 55 and the inner surface 56 of the sleeve 14. The plurality of openings 150 are sufficiently open when the sleeve 14 is in a compressed state. In one embodiment, the plurality of openings 150 provide a total surface area of the outer surface 55 of the sleeve 14 when the sleeve 14 is in compression (ie, total surface area = surface area of the rail 44 at the outer surface 55 + surface area of the rib 46 at the outer surface 55. + The area of the outer surface 55 of the sleeve 14 that is greater than about 40% of the area of the opening 150 in the outer surface 55). In other embodiments, the plurality of openings 150 define an area of the outer surface 55 of the sleeve 14 that is about 50% or more of the total surface area of the outer surface 55 of the sleeve 14 when the sleeve 14 is in a compressed state. In other embodiments, the plurality of openings 150 define an area of the outer surface 55 of the sleeve 14 that is about 60% or more of the total surface area of the outer surface 55 of the sleeve 14 when the sleeve 14 is in a compressed state. In other embodiments, the plurality of openings 150 define an area of the outer surface 55 of the sleeve 14 that is about 70% or more of the total surface area of the outer surface 55 of the sleeve 14 when the sleeve 14 is in a compressed state. In other embodiments, the plurality of openings 150 are areas of the outer surface 55 of the sleeve 14 that range from about 40% to about 95% of the total surface area of the outer surface 55 of the sleeve 14 when the sleeve 14 is in a compressed state. Is specified.

  The covering 32 of the expandable and foldable structure 12 is first present in the opening 150 of the sleeve 14. It will be appreciated that “first” is, for some coverings 32, between the rails 44 and the outer surface 22 of the expandable and foldable structure 12, as well as the ribs 46 and the expanded and folded. Located between the outer surfaces 22 of the possible structures 12. When the covering 32 is first present between the openings 150 in the sleeve 14, the size of the openings 150 and the first thickness of the rail 44 cooperate to provide a target site by the catheter assembly 10. Defines the amount of coating 32 that can be carried. In the subject embodiment, the outer diameter of the covering 32 is less than the outer diameter of the sleeve 14 when the expandable and foldable structure 12 is in a contracted state and the sleeve 14 is in a compressed state. As the first thickness of the rail 44 increases, the thickness of the covering 32 can increase.

  Referring to FIGS. 14-16, the catheter assembly 10 is guided according to a guidewire 28 to a target site in the patient's body. When the catheter assembly 10 is guided according to the guide wire 28, the catheter assembly 10 is placed in the inner bore 152 of the guide tube 154.

  As best shown in FIGS. 15 and 16, the catheter assembly 10 may contact the inner wall 156 of the guide tube 154 when the catheter assembly 10 is guided to the target site. The sleeve 14 is configured to protect the covering 32 of the catheter assembly 10 as it moves to the target site of the catheter assembly 10. When the sleeve 14 is in compression, the rail 44 of the sleeve 14 reduces the amount of direct contact between the sheath 32 and the inner wall 156 if the outer diameter of the sleeve 44 rail 44 is greater than the outer diameter of the sheath 32. To reduce or reduce. As the catheter assembly 10 moves to the target site, the inner wall 156 of the guide tube 154 contacts the outer surface 55 of the rail 44 rather than the covering 32. Many coatings 32 are available for delivery to the target site as a direct contact between the catheter assembly 10 and the guide tube 154 because a small number of coatings are lost during delivery to the target site.

  With reference to FIGS. 17 and 18, the use of the catheter assembly 10 is described. When the catheter assembly 10 is positioned at a target site within the patient's body, fluid can enter the lumen 30 of the expandable and foldable structure 12 such that the expandable and foldable structure 12 expands into an expanded state. Reportedly. The fluid pressure creates a force against the inner surface 24 of the expandable and foldable structure 12 causing expansion of the expandable and foldable structure 12. In one embodiment, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is approximately 15 atmospheres or less. In one embodiment, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is approximately 10 atmospheres or less. In other embodiments, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is in the range of approximately 5 to 10 atmospheres. In other embodiments, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is in the range of approximately 7 to 10 atmospheres.

  In the embodiment depicted in FIG. 17, the second expandable and collapsible structure 140 is also expanded to the expanded state. In one embodiment, the second expandable and foldable structure 140 is expanded prior to expansion of the expandable and foldable structure 12. In one embodiment, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is approximately 5 atmospheres or less. In one embodiment, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is approximately 3 atmospheres or less. In other embodiments, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is in the range of approximately 1 to 5 atmospheres. In other embodiments, the fluid pressure required to expand the expandable and foldable structure 12 to an expanded state is in the range of approximately 2 to 3 atmospheres.

  The fluid force against the inner surface 24 of the expandable and collapsible structure 12 is acting against the inner surface 56 of the sleeve 14 and causes the sleeve 14 to expand radially outward into an expanded state. When the sleeve 14 is expanded, the area of the opening 150 in the outer surface 55 of the sleeve 14 increases. This increase in area causes contact with the target site in the patient's body due to the increased amount of covering 32.

  As best shown in FIG. 18, with the expandable and foldable structure 12 and sleeve 14 expanded, the covering 32 expands through an opening 150 in the sleeve 14. In the depicted embodiment, the covering 32 extends past the outer surface 55 of the sleeve 14. Expansion of the covering 32 past the outer surface 55 of the sleeve 14 causes the covering 32 to contact the location of the target site in the patient's body or surrounding tissue. With the coating 32 in contact with or around the target site within the patient's body, the bioactive agent is delivered to or around the target site.

  After the bioactive agent of at least a portion of the covering 32 is delivered, the fluid in the lumen 30 of the expandable and foldable structure 12 is drained. The force acting against the inner surface 56 of the sleeve 14 with the fluid in the lumen 30 removed is removed. When the original shape memory alloy of the sleeve 14 is in a compressed state, the sleeve 14 naturally contracts into a compressed state when the fluid in the lumen 30 of the expandable and foldable structure 12 is drained.

  The temperature of the sleeve 14 needs to be adjusted before the sleeve 14 naturally contracts. In one embodiment, the temperature of the sleeve 14 can be adjusted by sending warm liquid through the lumen 30 of the expandable and foldable structure 12.

  When the sleeve 14 contracts to a compressed state, the expandable and foldable structure 12 contracts to a contracted state. Once the expandable and collapsible structure 12 and the sleeve 14 are contracted and compressed, respectively, the catheter assembly 10 passes through the guide tube 154 (shown in FIG. 14) and passes through the vasculature within the patient's body. Removed from the patient and withdrawn from the patient.

  Various changes and modifications of this disclosure will become apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Of course, the scope of the present disclosure is not limited to the corners of the embodiments described herein.

FIG. 6 is a side view of a catheter assembly having exemplary features of embodiments in accordance with the principles of the present disclosure, with the expandable and foldable structure in a contracted state and the sleeve in a compressed state. It is sectional drawing of the catheter assembly in the 2-2 line of FIG. FIG. 3 is a cross-sectional view of the catheter assembly taken along line 3-3 in FIG. 2. FIG. 2 is a cross-sectional view of the catheter assembly of FIG. 1 showing an optional protective layer. FIG. 5 is a cross-sectional view of the catheter assembly taken along line 5-5 in FIG. FIG. 2 is a cross-sectional view of the catheter assembly of FIG. 1 showing an optional release layer. FIG. 2 is a cross-sectional view of the catheter assembly of FIG. 1 showing an optional second protective layer. FIG. 10 is a side view of another embodiment of a sleeve in a catheter assembly. FIG. 10 is a side view of another embodiment of a sleeve in a catheter assembly. FIG. 10 is a side view of another embodiment of a sleeve in a catheter assembly. FIG. 10 is a side view of a catheter assembly showing an alternative connection arrangement between an expandable and foldable structure and a sleeve. FIG. 10 is a side view of a catheter assembly showing an alternative connection arrangement between an expandable and foldable structure and a sleeve. FIG. 10 is a side view of a catheter assembly showing a second expandable and collapsible structure. FIG. 10 is a side view of a catheter assembly having an expandable and foldable structure in an expanded state and a sleeve in an expanded state. FIG. 15 is a cross-sectional view of the catheter assembly taken along line 15-15 of FIG. FIG. 6 is a cross-sectional view of a catheter assembly in which a guide tube is disposed. FIG. 10 is another cross-sectional view of a catheter assembly in which a guide tube is disposed. FIG. 10 is another cross-sectional view of a catheter assembly in which a guide tube is disposed.

Claims (40)

An expandable and foldable structure having an outer surface and configured to expand between a contracted state and an expanded state;
A coating disposed on the outer surface of the expandable and foldable structure, the coating comprising a bioactive agent;
A sleeve made of a shape memory alloy disposed on one surface of the covering, which expands between a compressed state and an expanded state in response to a force acting on the inner surface of the sleeve, and when the force is removed, the expansion A sleeve configured to return from the state to the compressed state, and in the compressed state, the sleeve defining a plurality of openings,
When the expandable and foldable structure is in the contracted state, the outer diameter of the covering is smaller than the outer diameter of the sleeve, and when the expandable and foldable structure is in the expanded state, the covering A catheter assembly wherein the outer diameter of the sleeve is greater than the outer diameter of the sleeve. The sleeve is
A first axial end and a second axial end disposed on the opposite side;
An outer surface extending between the first and second axial ends;
An inner surface defining a bore extending between the first and second axial ends and in which the expandable and foldable structure is disposed;
A plurality of rails extending between the first and second axial ends and defining the plurality of openings;
The catheter assembly according to claim 1, wherein the plurality of openings extend through the inner surface and the outer surface.   The catheter assembly according to claim 2, wherein the plurality of rails are the first and second axial ends.   The catheter assembly according to claim 3, wherein the sleeve includes a plurality of ribs extending between adjacent rails.   The catheter assembly according to claim 4, wherein the plurality of ribs are arranged at an inclination angle with respect to the plurality of rails.   The catheter assembly of claim 1, wherein the sleeve material comprises a nickel-titanium alloy.   The catheter assembly of claim 1, wherein the coating softens or dissolves at a temperature between room temperature and body temperature.   2. The coating according to claim 1, wherein the coating includes a drug coating with a bioactive agent and a protective coating with a fatty acid, the protective coating being disposed on the drug coating. Catheter assembly.   The catheter assembly according to claim 8, wherein the protective covering comprises a plurality of fatty acids.   The catheter assembly according to claim 9, wherein the plurality of fatty acids are solid at room temperature and are soft or liquid at the body temperature of the subject.   The catheter assembly of claim 1, further comprising a second expandable and collapsible structure disposed adjacent to a proximal end of the expandable and collapsible structure. An expandable and foldable structure having an outer surface and configured to expand between a contracted state and an expanded state;
A drug coating disposed on the outer surface of the expandable and foldable structure and comprising a bioactive agent;
A protective coating disposed on the drug coating and comprising a mixture of a plurality of fatty acids;
A sleeve made of a shape memory alloy, disposed on one surface of the protective covering, expands between a compressed state and an expanded state according to the force acting on the inner surface of the sleeve, and when the force is removed, A sleeve configured to return from the expanded state to the compressed state, wherein the sleeve expands longitudinally between a first axial end and a second axial end disposed on the opposite side. A plurality of rails, wherein the plurality of rails define a plurality of openings, and the protective covering is accessible through the plurality of openings in a compressed state, each of the plurality of openings The size of the catheter assembly increases in the expanded state.   The catheter assembly of claim 12, wherein the sleeve material comprises a nickel-titanium alloy.   The catheter assembly according to claim 12, wherein the sleeve includes a plurality of ribs extending between adjacent rails.   The catheter assembly according to claim 14, wherein the plurality of ribs are arranged at an inclination angle with respect to the plurality of rails.   13. The catheter assembly of claim 12, wherein the fatty acid mixture is solid at room temperature and soft or liquid at the body temperature of the subject.   The catheter assembly according to claim 16, wherein the mixture of fatty acids comprises oleic acid, dodecanoic acid, or salts thereof.   The catheter assembly of claim 12, wherein the bioactive agent comprises an antiproliferative agent, an anti-inflammatory agent, or an antiplatelet agent.   A free coating material disposed between the outer surface of the expandable and foldable structure and the drug coating, wherein the free coating material is configured to facilitate the release of the drug coating. The catheter assembly of claim 12.   The catheter assembly of claim 12, further comprising a second expandable and foldable structure disposed adjacent to a proximal end of the expandable and foldable structure. An expandable and foldable structure having an outer surface and configured to expand between a contracted state and an expanded state;
A coating disposed on the outer surface of the expandable and foldable structure, the coating comprising a bioactive agent;
A sleeve made of a shape memory alloy disposed on one surface of the covering, which expands between a compressed state and an expanded state in response to a force acting on the inner surface of the sleeve, and when the force is removed, the expansion A sleeve configured to return from a state to the compressed state, the sleeve comprising:
Including a body having an inner surface and an outer surface;
The inner surface defines a bore in which the expandable and foldable structure is disposed;
The body defines a plurality of openings extending through the inner surface and the outer surface, wherein the plurality of openings is about 40% to about 95% of the total surface area of the outer surface in the compressed state. A catheter assembly that defines an area of the outer surface in a compressed state.   The catheter assembly of claim 21, wherein the sleeve material comprises a nickel-titanium alloy.   23. The catheter assembly of claim 22, wherein the body of the sleeve includes a plurality of rails that extend between a first end of the body and a second end of the body disposed oppositely. .   24. The catheter assembly of claim 23, wherein the body includes a plurality of ribs that extend between adjacent rails.   The catheter assembly according to claim 21, wherein the coating includes a drug coating having the bioactive agent and a lipid coating disposed on the drug coating. A main body having a first axial end, a second axial end disposed on the opposite side, an outer surface, and an inner surface disposed on the opposite side, the main body comprising the first and second axial ends; A bore that extends through a portion and a plurality of openings that pass through the outer surface and the inner surface, and the body is biased to a compressed state as compared to an expanded state, and reacts to forces acting on the inner surface The expanded state is formed, and the main body is configured to return from the expanded state to the compressed state when the force is removed, and the plurality of openings are formed on the entire outer surface in the compressed state. A sleeve of shape memory alloy of a catheter assembly that defines an area of the outer surface in the compressed state that is from about 40% to about 95% of the surface area.   27. The sleeve of claim 26, wherein the body includes a plurality of rails disposed between the first and second axial ends.   28. The sleeve of claim 27, wherein each of the plurality of rails forms an annular ring.   30. The sleeve of claim 28, wherein each of the plurality of rails includes a relief.   30. The sleeve of claim 29, wherein the body includes a plurality of ribs coupled to adjacent rails.   The sleeve of claim 30, wherein each of the ribs includes a relief.   27. The sleeve of claim 26, wherein the body includes a plurality of rails that extend between the first and second axial ends.   The sleeve of claim 32, wherein each of the plurality of rails includes a relief.   The sleeve according to claim 33, wherein the undulations are typically sinusoidal in shape.   The sleeve of claim 32, wherein each of the plurality of rails is normally parallel to an adjacent rail in the compressed state.   33. The sleeve of claim 32, wherein each of the plurality of rails is arranged in a spiral around the central longitudinal axis of the body in the compressed state.   33. The sleeve of claim 32, wherein the body includes a plurality of ribs that extend between adjacent rails.   38. The sleeve of claim 37, wherein each of the plurality of ribs includes a relief.   27. The sleeve of claim 26, wherein the body material comprises a nickel-titanium alloy. An expandable and foldable structure having an outer surface, configured to expand between a contracted state and an expanded state, and having a distal end and a proximal end disposed oppositely; ,
A sleeve made of a shape memory alloy disposed around the outer surface of the expandable and foldable structure, the sleeve having a first axial end and a second axial direction disposed on the opposite side. Including a body having an end, an outer surface, and an oppositely disposed inner surface, wherein the body defines a bore in which at least a portion of the expandable and foldable structure is disposed, the bore comprising: Expanding through the first and second axial ends, the body defining a plurality of openings through the outer surface and the inner surface, the body being expandable and foldable in the expanded state The structure expands from the compressed state to the expanded state in response to the force applied to the inner surface of the sleeve provided by the flexible structure, the force is removed, and the expandable and foldable structure is in the contracted state. An area of the outer surface in the compressed state that is configured to return from the expanded state to the compressed state, wherein the plurality of openings are about 40% to about 95% of the total surface area of the outer surface in the compressed state. Prescribing a catheter assembly.

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